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INVITED REVIEW

Vascular endothelial growth factor in the lung

¹University of Colorado Health Sciences Center, Pulmonary and Critical Care Division, Denver, Colorado; and ²Divisions of Cardiopulmonary Pathology and Pulmonary and Critical Care Medicine, Departments of Pathology and Medicine, Johns Hopkins University, Baltimore, Maryland

	ABSTRACT

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Vascular endothelial growth factor (VEGF) is a pluripotent growth and permeability factor that has a broad impact on endothelial cell function. The lung tissue is very rich in this protein; many different lung cells produce VEGF and also respond to VEGF. VEGF is critical for the development of the lung and serves as a maintenance factor during adult life. In addition to the physiological functions of this protein, there is increasing evidence that VEGF also plays a role in several acute and chronic lung diseases, such as acute lung injury, severe pulmonary hypertension, and emphysema. Here we provide a comprehensive overview of the rapidly expanding literature.

	BIOLOGICAL ACTIVITIES OF VEGF

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
In the lung, VEGF functions as a mitogen, survival, and differentiation factor for endothelial cells (55). The growth properties of VEGF have been demonstrated in in vitro and in vivo systems. However, the relative contribution of VEGF to endothelial cell growth is organ and context specific, i.e., some endothelial cells respond more robustly to VEGF when cultured under semiconfluent conditions or when they engage in angiogenic activity in tumors or corpus luteum development. Several critical gene products are activated downstream of VEGF (68, 201), which play a contributory role in VEGF-induced angiogenesis and endothelial cell growth. Under specific conditions, particularly those related to tumor vessels, VEGF is a potent permeability factor (163).

Our knowledge of the scope of VEGF's actions on endothelial cells expanded significantly with the identification of the prosurvival functions of this growth factor in vitro (5, 54, 55, 60) and in seminal studies that explored retinopathy of prematurity and cancer angiogenesis (5, 12).

VEGF profoundly affects several functional properties of endothelial cells, highly relevant to lung function and pulmonary vascular properties, such as nitric oxide (NO) and prostacyclin synthesis. The production of NO and PGI₂ leads to vasodilation, as demonstrated in the pulmonary circulation and coronary arteries (117), and systemic hypotension (56). VEGF activates endothelial cell NO synthase (81, 187), which in turn mediates the proangiogenic effects of VEGF (43). NO also mediates the permeability effects of VEGF (62), possibly involving src or Yes kinases (49). The survival properties of VEGF rely on activation of Bcl-2 (69), survivin, inhibitors of apoptosis (50), and vessel morphogenesis, on the activity of the integrin-linked kinase (105), and on serum-response factor (23).

In addition and importantly, several nonendothelial cells also express VEGFRs and bind VEGF (Table 1), which then triggers cell growth and survival. For example, type II pneumocytes undergo growth and differentiation in the presence of VEGF (15, 32). VEGF affects neuronal cells, pancreatic cells, mobilization, and survival of bone marrow progenitor cells (71, 79), and as discussed below, activation of immune cells (25). Interestingly, there is an age-dependent progressive loss of prosurvival effects of VEGF on endothelial and bone marrow progenitor cells (158) that may also impact on aging of the lung.

	TRANSCRIPTIONAL CONTROL OF VEGF GENE

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

VEGF is a prototypic member of hypoxia-inducible genes (168). The transcriptional control resides in a key region of the promoter at approximately –930 from the transcriptional start site in a 50-bp region responsive to hypoxia, oncoproteins like c-Myc (140), and growth factor activators (101, 114). This region binds to a heterodimer of hypoxia-inducible factor-1 (HIF-1) (162) and aryl hydrocarbon nuclear translocator (ARNT or HIF-1). HIF-1 stability, the rate-limiting step in the activation of the heterodimer transcription factor, relies on reduced proline hydroxylation by decreased proline hydroxylase activity due to low oxygen (8, 162). The lack of proline hydroxylation renders HIF-1 resistant to binding of the von Hippel-Lindau protein and proteosome-mediated degradation (72, 96).

A wide range of growth factors such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)- and -, insulin growth factor-I, fibroblast growth factor, and keratinocyte growth factor stimulate VEGF synthesis (2, 53, 102, 156). The fact that platelet-activating factor (PAF) production is stimulated by VEGF (2) illustrates the tight link between inflammation and angiogenesis (98). Estrogens increase VEGF transcription (95, 130) via binding of the estrogen receptor to cognate response elements (142, 209). IL-1 and PDGF increase VEGF mRNA expression (Fig. 1). Five VEGF gene promoter region polymorphisms have been identified (14), and attempts have been made to associate gene polymorphisms with renal transplant rejection (164), Kawasaki disease (107), and with the risk of smoking-related chronic obstructive pulmonary disease (COPD) (160).

View larger version (15K): [in this window] [in a new window]   Fig. 1. The complexity of VEGF transcriptional control. Not only is hypoxia involved, but also involved are cytokines, endotoxin, and estrogen. PI3K, phosphatidylinositol 3-kinase; HIF, hypoxia-inducible factor; HHV, human herpesvirus; STAT3, signal transducer and activator of transcription-3; GPCR, G protein-controlled receptor; V-SRC, viral SRC; C-Myc, an oncoprotein; LIF, leukemia inhibitory factor.

	PlGF

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

	VEGFRS

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
The VEGF family signals through three different receptors (81, 97, 99, 181, 182). VEGF-A binds to VEGFR-1 and VEGFR-2. These receptors interact and modify the biological effects of VEGF either positively or negatively, depending on the specific vascular bed, the experimental condition, and disease state.

Since its discovery by Terman et al. (181), VEGFR-2 or kinase domain receptor (KDR, human receptor) or fetal liver kinase-1 (the rodent ortholog receptor) has accounted for most VEGF effects on endothelial cells, such as cell proliferation, NO and prostacyclin production, angiogenesis, and vascular permeability (81, 182). VEGFR-2 (KDR) was first cloned from a human endothelial cell cDNA library due to its homology to the PDGF receptors, and expression of this receptor was detected in endothelial but not smooth muscle cells (97). The genetic locus of the KDR gene is human chromosome 4 (99). Ligand binding was found to be inhibited by heparinase and restored by addition of heparin (181). VEGFR-2 knockout mice are embryonic lethal, lacking both vasculogenesis and angiogenesis, indicative of a fundamental role of VEGFR-2 in vascular biology (165). VEGF ligand binding to VEGFR-2 and cell signaling via the phosphatidylinositol 3-kinase/Akt pathway control endothelial cell survival (200). Activation of endothelial NO synthase via c-Src and phospholipase C 1 (PLC1) and activation of prostacyclin synthase via MAPK lead to increased endothelial cell NO and PGI₂ production, respectively (Fig. 2), which may contribute to endothelial cell survival. NO upregulation due to VEGF may also participate in the increased generation and mobilization of endothelial cell progenitor cells (3). The transcriptional control of the VEGFRs is complex. Hypoxia increases KDR (VEGFR-2) gene expression (8, 24, 189) perhaps via generation and action of TNF- (155).

View larger version (16K): [in this window] [in a new window]   Fig. 2. In endothelial cells, VEGF ligand binding to the VEGF receptor-2 tyrosine kinase leads to upregulated expression of endothelial nitric oxide (NO) synthase and NO production and to increased prostacyclin production. Prostacyclin feeds back and upregulates VEGF gene expression via PKA. KDR, kinase domain receptor; DAG, diacylglycerol; PGI2-S, prostacyclin synthase; PKC, protein kinase C; PKA, protein kinase A; PIP3, phosphoinositol 3,4,5-phosphate; IP3, inositol triphosphate.

Waltenberger et al. (200) were the first to show that VEGFR-1 (Flt-1) and VEGFR-2 (KDR) transduce different VEGF-dependent cellular events. VEGFR-1 (Flt-1) is essential for the organization of the embryonic vasculature since embryos of VEGFR-1 knockout mice assemble endothelial cell tubes as abnormal vascular channels and die in utero due to lack of the structural organization of the vessel walls (57). Because VEGFR-1 relays poor growth-promoting signals and is weakly phosphorylated, early investigation of the roles of each VEGFR signaling indicated that VEGFR-1 might act as a silent receptor for VEGF, since its kinase activity is weak, and its downstream signaling is poorly delineated (200). VEGFR-1 might repress most of the endothelial cell effects of VEGF/VEGFR-2 signaling by serving as a decoy for VEGF (21), as documented by the excess endothelial cells in amniotic membrane vessels of embryos knocked out for VEGFR-1 but with intact VEGFR-2 (111). In addition, VEGFR-1, but not VEGFR-2, mediates the increase in monocyte adhesion to VEGF-treated endothelial cells (111) and induces expression of tissue factor by endothelial cells (128).

Recent evidence indicates that VEGFR-1 enhances VEGF-induced VEGFR-2 signaling during angiogenesis in several pathological conditions (21). Mice deficient in PlGF-1, which exclusively binds to VEGFR-1, show normal vascular development but have an impaired angiogenic and edematogenic response during ischemia, inflammation, wound healing, and cancer (21). In fact, the combination of PlGF-1 and VEGF, but not PlGF-1 alone, strongly induced capillary sprouting in aortic rings of PlGF-1 mice. There is evidence that VEGFR-1 activation stimulates MMP-9 as mentioned. Metastatic seeding to the lung requires VEGFR-1-dependent activation of MMP-9 in the lung microcirculation. PlGF-1, in a VEGFR-1-dependent manner, enhances mobilization of hematopoietic stem cells during reconstitution of bone marrow after ablation via enhancement of cell motility (as observed with monocytes) and by VEGFR-1-mediated activation of MMP-9, causing release of c-kit (79).

The soluble variant of VEGFR-1 (or s-Flt) adds another layer of complexity to VEGFR signaling (11, 89, 112). This soluble variant may decrease the bioavailability of VEGF (89) in pathobiological conditions such as preeclampsia (138).

	VEGF-INDUCED CELL SIGNALING

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Upon ligand binding, VEGFRs undergo dimerization, assembly of a signaling complex and a signaling cascade ultimately leading to cell-specific effects. VEGF binding to VEGFR-1 leads to phosphorylation of tyrosine residue 1213 (whereas PlGF binding results in phosphorylation of residue 1309) (9). VEGFR-2 activation results in autophosphorylation of several tyrosine residues in the kinase insert domain, followed by binding of proteins containing the Src homology-2 domain with phosphotyrosines. VEGFR-2-triggered cell proliferation involves activation of the Erk pathway and association with vascular-endothelial cadherin. This association releases phosphorylated -catenin to translocate to the nucleus and mediates lymphoid-enhancer factor-induced gene transcription. -Catenin, and therefore the Wnt-pathway, plays a role in angiogenesis, as it increases VEGF gene and protein expression in endothelial cells and the phosphorylation of VEGFR-2 (169). VEGFR-2-mediated activation of the phosphatidylinositol 3-kinase/Akt pathway mediates endothelial cell survival (60), phosphorylates and inactivates caspase-9 (19) and Bad (37), and increases NO production by endothelial cells via NO synthase activation (43). Ligand binding to VEGFR-2 is followed by activation of focal adhesion kinases, p38 MAPK, and paxillin, thus enabling endothelial cell migration (36). Its interaction with src and Yes tyrosine kinases mediate VEGF-induced permeability (47).

	ROLE OF VEGF IN LUNG DEVELOPMENT AND FETAL DISTRESS SYNDROME

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
The VEGF signaling pathway has been shown to play a critical role in embryonic vasculogenesis (Gebb S, Tuder RM, Voelkel NF, Abman SH, unpublished observations; 66), particularly during fetal lung development. Vessel development in the early lung determines lung structure maturation, and both undisturbed angiogenesis and vasculogenesis are necessary for the successful building of the organ (82). The hypoxic environment of the developing lung favors HIF-1-dependent gene expression (210), and HIF-2 also controls expression of the VEGF₁₆₄ and VEGF₁₈₈ isoforms in the developing lung (4).

Overall the roles of VEGF during lung development are likely complex and multilayered, including increased PAF expression and PKC activation. VEGF and VEGFR-2 expression can be demonstrated in branching tubular airways and in vascular mesenchymal cells during fetal development and in vitro in reconstituted cultures containing lung fetal epithelial and mesenchymal elements (66). Furthermore, isolated mesenchymal elements undergo regression and lack of growth with collapse of the branching pulmonary arteries (200). The coordinated building of airway epithelial and endothelial lung cell compartments requires a VEGF gradient, being produced in the tips of the growing airway tubular structures (82). The levels of fetal lung VEGF are of critical importance since lung VEGF overexpression, particularly when targeted to peripheral epithelial cells, causes lung dysmorphogenesis (4, 200), whereas a decrease in lung VEGF as a consequence of neutralization of VEGF or VEGF gene deletion using a Cre-Lox approach resulted in poor septal formation and an emphysematous pattern (70). Expression of the soluble VEGF₁₂₁ form in the absence of the other isoforms of VEGF equally caused respiratory distress and poor lung development in mice (20). VEGF not only acts as a growth and morphogenetic factor for lung endothelial cells but also acts on type II pneumocytes. Type II cells express VEGFR-2 (15, 31, 32), and VEGF enhances type II pneumocyte growth (133), although this effect may be indirect since VEGF₁₆₅ did not induce cell growth of cultured fetal type II cells nor did it increase its surfactant production (157). Alveolar type II cells express KDR (51), and VEGF increases surfactant protein B and C VEGFR-2 dependently (32). Not only does VEGFR inhibition lead to inhibition of angiogenesis and alveolarization in the developing rat lung (100), which persists into adulthood (123), but short-term VEGFR blockade also reduces the number of so-called blood islands and platelet endothelial cell adhesion molecule- and KDR-positive endothelial cells in the fetal rat lung explant preparation (Gebb S, Tuder RM, Voelkel NF, Abman SH, unpublished observations).

Consistent with the critical role of endothelial cells and VEGF during lung development, strategies to disrupt fetal and perinatal VEGF signaling result in respiratory distress and bronchopulmonary dysplasia (13). High doses of dexamethasone suppress VEGF levels (45) and VEGFR-2 expression (31) in the developing lung and cause emphysema in adult rats (27), as VEGF is apparently essential for both endothelial and epithelial cell growth in the lung. VEGFR inhibition with a combined VEGFR-1 and VEGFR-2 blocker, SU-5416, led to lung immaturity (100) in rats, which persisted into adult life and caused pulmonary hypertension (123). These observations were confirmed in studies involving HIF-2^+/– mice, which showed defective surfactant production, alveolar septal vessel deficit, and respiratory distress at birth that can be rescued with VEGF (32).

The increase in fetal lung levels of VEGF, VEGFR-1, and VEGFR-2 continues in the perinatal lung, reaching approximately twofold levels over those at postnatal day 6, and is paralleled in rodents by a concomitant increase in HIF-2 (91). However, during the critical period of perinatal lung adaptation to postnatal life, there is a requirement of normal VEGF lung levels and VEGFR-2 signaling. Overexpression of VEGF caused by tetracycline induction of a conditional VEGF promoter causes lung injury, with emphysematous lesions and hemorrhage (124). We have recently observed that VEGFR-2 neutralization with a monoclonal rat antibody during the first week of life causes alveolar injury with air space enlargement, which is temporary and is followed by recovery within the first month of life.

The realization of the importance of VEGF in fetal lung growth led to a vascular theory of bronchopulmonary dysplasia. Bronchopulmonary dysplasia results from injury to the alveolar cells, leading to respiratory distress (152). Bronchopulmonary dysplasia continues to be an important consequence of lung injury due to prematurity, mechanical ventilation, and hyperoxia treatment for lung distress during perinatal life. Bhatt et al. (13) showed decreased VEGF, VEGFR-1, and Tie-2 expression in lungs from infants dying with bronchopulmonary dysplasia. These findings were later confirmed by Lassus et al. (120), who also described decreased expression of VEGFR-1.

Hyperoxia is one of the main contributors to bronchopulmonary dysplasia. Hyperoxia decreases lung levels of VEGF (135). Klekamp et al. (115) documented a reduction of VEGF in lungs of rats exposed to hyperoxia, associated with alveolar cell apoptosis and reduction of VEGFR-2 and VEGFR-1 expression. Hyperoxia (>95% between postnatal days 6 and 14) dramatically reduced VEGF, VEGFR-1, and VEGFR-2 lung expression levels (91). Interestingly, inhibition of VEGFR-2, but not VEGFR-1, during the first week of life recapitulates the alveolar growth arrest seen with hyperoxia. However, in contrast to hyperoxia, these changes are reversible (McGrath S and Tuder RM, unpublished observations). Hyperoxia may thus lead to persistent lung injury by means of a more widespread alveolar injury, permanently jeopardizing the lung cells ability to synthesize VEGF and/or respond via VEGFR-2.

	PULMONARY HYPERTENSION

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Pulmonary hypertension is associated with changes in vascular cell size (hypertrophy) and number (hyperplasia) involving all three cell types within the small precapillary pulmonary arteries, endothelial cells, smooth muscle cells, and adventitial fibroblasts. The importance of growth factors in pulmonary hypertension has not been completely elucidated since they may have disparate roles when comparing early vs. late disease and experimental vs. human pulmonary hypertension (208).

Subsets of patients with idiopathic pulmonary hypertension and severe pulmonary hypertension associated with congenital heart malformations, human immunodeficiency virus infection, liver disease, and collagen vascular disease present with abnormal proliferation of endothelial cells, forming plexiform lesions (190, 191, 199). Although germline mutations in bone morphogenetic protein receptor-2 and somatic inactivating mutations of transforming growth factor receptor-2 have been described in the disease (41, 118), angiogenic factors are likely instrumental in the abnormal growth of endothelial cells in pulmonary hypertension. VEGF is strongly expressed in the angioproliferative plexiform lesions in the lungs from patients with severe primary idiopathic and secondary forms of pulmonary hypertension (67, 84, 190), including children with various forms of congenital heart diseases (67), persistent pulmonary hypertension of the newborn (121), and infants with pulmonary hypertension in the setting of congenital diaphragmatic hernias (167).

VEGF has been linked as potentially causative to the etiology of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS syndrome)-associated pulmonary hypertension, as based on a case report (147), and in patients with human herpesvirus-8 infection and severe pulmonary hypertension (33). Here, the virus, regional ischemia, and cytokines could be responsible for VEGF overexpression.

In contrast to human pulmonary angioproliferative disease (206), animal models reflect mostly the milder forms of pulmonary hypertension but allow the investigation of the role of a given growth factor in the initiation and progression of the disease (198). Table 2 lists the published results of pulmonary hypertension animal models where VEGF mRNA and/or protein levels had been measured in the lung or VEGF expression in the lung had been manipulated. Given VEGF-dependent endothelial cell PGI₂ and NO production, one might predict that VEGF modulates hypoxic pulmonary vasoconstriction and pulmonary hypertension, a concept that has been verified experimentally. VEGF gene and protein expression is upregulated in the lung tissue after short- and long-term hypoxic exposure of animals (153). There is now a consensus that chronic hypoxia increases lung tissue VEGF expression and that VEGF is likely a modulator of chronic hypoxia-induced pulmonary vascular remodeling (154). In contrast, in the monocrotaline rat model of pulmonary hypertension, VEGF tissue expression appears to be decreased (153). VEGF overexpression protects against hypoxic (154) and monocrotaline-induced pulmonary hypertension (18). Interestingly, VEGF-B, in contrast to VEGF-A, enhances hypoxic pulmonary hypertension since knockouts were protected against elevation of pulmonary artery pressures and pulmonary vessel remodeling when compared with wild-type mice (202). A similar observation has been made with regard to PlGF knockout mice (21). This finding may be related to VEGF-B (like PlGF) binding to VEGFR-1 expressed by smooth muscle cells, inducing MMP-9, smooth muscle cell migration, and blood vessel remodeling (75). However, Louzier et al. (131) reported that VEGF-B knockouts developed similar hypoxic pulmonary hypertension as wild-type mice and that VEGF-B overexpression protected against pulmonary hypertension in a NO synthase-independent manner.

Interestingly, mice carrying only a single functional copy of the HIF-1 or HIF-2 genes demonstrate impaired hypoxia-induced pulmonary remodeling and diminished pulmonary hypertension (16, 207); HIF-1^–/+ animals have pulmonary arterial smooth muscle cells that are electrophysiologically different, indicating that hypoxia sensing and hypoxic vasoconstriction are HIF-1 dependent (207). Whether VEGF levels and signaling via KDR is altered in the lungs of HIF-1^–/+ animals is unknown.

Last, we have described a rat model of severe pulmonary hypertension (178) caused by the combination of chronic VEGFR blockade by the small molecule tyrosine kinase inhibitor SU-5416 and chronic alveolar hypoxia. The pulmonary artery mean pressure in these animals is in excess of 60 mmHg, and precapillary arterioles are obliterated by proliferated endothelial cells. Because concomitant treatment of the animals with a broad-spectrum caspase inhibitor prevents the development both of severe pulmonary hypertension and of the vascular lesions (178), we postulate that vigorous endovascular proliferation is the consequence of significant initial endothelial cell apoptosis induced by SU-5416. Initial blockade of VEGFRs and VEGF signal transduction, which are critical for pulmonary endothelial cell survival, might have allowed for the subsequent emergence of an apoptosis-resistant, hyperproliferative vascular cell phenotype (191). Locally increased shear stress may contribute to this abnormal endothelial cell growth.

This model has been used by us to develop novel treatment strategies aimed at the severe angioproliferative component of pulmonary hypertension. Both bradykinin receptor II agonist and simvastatin have so far been shown as effective treatments of pulmonary hypertension in this SU-5416/chronic hypoxia model (Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder R, Burns N, Kasper M, Voelkel NF, unpublished observations). Of interest, the reduction by these agents in pulmonary artery pressure in this model was associated with partial reversal of the obliterative pulmonary artery lesions due to endothelial cell apoptosis (Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder R, Burns N, Kasper M, Voekel NF, unpublished observations).

	LUNG INJURY

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Acute lung injury and its more severe form, acute respiratory distress syndrome (ARDS), involve a disruption of the alveolar-capillary membranes, with local inflammation ultimately leading to alveolar flooding with serum proteins and edema fluid (28, 139). Infiltrating inflammatory cells such as monocytes and local matrix degradation might be sources of VEGF that can increase alveolar capillary permeability. Patients with ARDS showed increased plasma VEGF and increased production by peripheral blood mononuclear cells when compared with patients at risk, normal individuals, and ventilated patients (183). The increased plasma VEGF from ARDS patients might have mediated the increase in lung permeability since it accounted for 50% of the permeability activity of ARDS plasma on cultured endothelial cells. In contrast, lungs of patients with sepsis, also a trigger of acute lung injury, have significantly lower levels of VEGF isoforms 121 and 165 and VEGFR-2 (194). Because the latter study was performed with autopsied lungs, it is difficult to interpret whether the reduction in VEGF expression was present in vivo and whether it is part of the pathogenesis of septic shock.

	EMPHYSEMA

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Inflammation and protease/antiprotease imbalance are the concepts used to explain the pathogenesis of cigarette smoke-induced emphysema (166). However, these concepts have so far failed to explain the unique nature of alveolar septal destruction in emphysema and why other inflammatory lung diseases, for example, lobar pneumonia, do not cause destructive air space enlargement. The novel concept of disruption of a lung cellular and molecular maintenance program to explain emphysema was developed based on the finding that a decrease of VEGF and VEGFR-2 expression in the lung tissue was associated with emphysema and the presence of a large number of apoptotic alveolar cells (109). Subsequently, these studies were followed by several independent investigations confirming VEGF reduction in more severe forms of emphysema (104, 116). Kasahara et al. (108) showed that chronic inhibition of VEGFRs in adult rats caused emphysema, which was prevented by an inhibitor of caspases, i.e., of apoptosis, thus linking impaired lung tissue VEGF signaling to lung cell apoptosis and emphysema. These observations have been recently confirmed by a genetic deletion of lung VEGF using Cre recombinase expression after intratracheal adenovirus instillation (176). Both VEGFR-1 and VEGFR-2 signaling is required for lung structural maintenance since inhibition of both receptors with neutralizing antibodies causes more pronounced emphysema than inhibition of each receptor alone (Tuder RM and McGrath S, unpublished observations).

Emphysema caused by VEGFR blockade involves a feedback loop of apoptosis and oxidative stress, since inhibition of apoptosis decreases lung oxidative stress, and inhibition of oxidative stress prevents alveolar cell apoptosis and emphysema development (188). The progression of alveolar cell destruction in emphysema may also rest on a feedback loop of apoptosis, oxidative stress, and matrix proteolysis, leading to lung destruction, facilitating inflammation and further decreasing growth factor availability and action in the emphysematous lungs (192).

Disruption of VEGF signaling, through either genetic deletion of lung VEGF (176) or VEGFR blockade (108), results in increased apoptosis of lung parenchyma cells and structural alterations characteristic of emphysema, suggesting that VEGF confers important survival signals necessary for the maintenance of the normal lung structure. The finding that human emphysema is also associated with increased apoptosis and decreased VEGF and VEGFR-2 supports this notion (109). However, these observations also suggest an alternative, complementary hypothesis, that VEGF is involved in the regulation of apoptotic cell removal and that dysregulated VEGF signaling impairs this process, resulting in the accumulation of apoptotic cells. This hypothesis is further supported by the findings that apoptotic cells are abundant in the sputum of patients with chronic bronchitis (195) and that alveolar macrophages taken from patients with COPD ingest apoptotic cells poorly (85).

Phagocytosis of apoptotic cells (efferocytosis) is a highly efficient process (203) integrally involved with the regulation of lung homeostasis and the inflammatory response (83, 180, 196, 197). Apoptotic cells target themselves for recognition and uptake into phagocytes by expressing surface ligands, in particular phosphatidylserine (49). A variety of phagocytic receptors recognize these ligands and ultimately direct efferocytosis (83). Downstream of these receptors, efferocytosis is tightly regulated by the Rho family of GTPases in that it is inhibited by RhoA and stimulated by Rac-1 or Cdc42 (87, 129, 184).

The net effect of efferocytosis is anti-inflammatory because 1) dying cells are removed before they undergo postapoptotic necrosis (78), 2) anti-inflammatory mediators are released, such as TGF-1, PGE₂, and IL-10 (48), and 3) adaptive immune responses are suppressed (88). These anti-inflammatory signals actively suppress IL-8, TNF-, and other inflammatory mediators (48, 94) that appear to be central in the pathogenesis of emphysema (38). Efferocytosis may also play a key role in tissue repair since it stimulates the release of anti-proteases (149) and growth factors, including hepatocyte growth factor (141) and VEGF (73). Therefore, defective efferocytosis may be particularly important in the pathogenesis of emphysema.

To determine whether VEGF or its receptors influence efferocytosis, macrophages were treated with the broad VEGFR inhibitor SU-5416. In these experiments, SU-5416 inhibited efferocytosis of apoptotic Jurkat T cells by human monocyte-derived macrophages in a dose-dependent manner. Because macrophages synthesize VEGF, which may act in an autocrine fashion to stimulate VEGFR-1, neutralizing antibodies against VEGF and VEGFR-1 were tested; both inhibited efferocytosis. In vivo, SU-5416 also inhibited clearance of apoptotic thymocytes after intratracheal administration in mice. Therefore, VEGF may perform a dual role in the lung by regulating both apoptosis and efferocytosis, such that disruption of VEGF signaling may dysregulate lung homeostasis and contribute to the pathogenesis of emphysema.

Alterations of VEGF lung tissue expression or VEGF signaling have been demonstrated in two rat models of emphysema. Decreased lung tissue VEGF protein expression can be shown in the new model of autoimmune emphysema (179), and altered Akt phosphorylation occurs in lungs of rats with steroid-induced emphysema (27). Whether VEGFR blockade or VEGF depletion results in generation of reactive oxidants in the endothelial cells is unclear, as is the temporal sequence of apoptosis, oxidant stress, and activation of matrix metalloproteinases (188). However, there is experimental evidence that VEGF upregulates MgSOD (1) and that apoptosis results in oxidative stress (113). In the steroid emphysema model, MMP-9 is overexpressed and VEGF signaling is impaired in the lung (27).

LPS has been shown to induce emphysema in rats (172), and, interestingly, LPS induces apoptosis of human lung microvascular cells, which can be inhibited by VEGF (143).

Finally, overexpression of PlGF in mice has been shown to be associated with significant emphysema (186). PlGF is abundantly expressed in lung tissue, and it regulates the cross talk between VEGFR-2 and VEGFR-1. PlGF overexpression in these mice was associated with air space enlargement at 6 mo of age; VEGF mRNA was decreased in the lungs, and apoptotic events were frequent in type II cells (186).

	ASTHMA

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
Because "asthma" is functionally defined as reversible airway obstruction associated with a variety of trigger factors, including exercise and aspirin sensitivity, this airway hyperreactivity in genetically susceptible individuals has focused most of the interest on inflammation and immune responses in the bronchi. Several groups have in recent years measured VEGF protein levels in bronchoalveolar lavage fluid from patients with asthma or examined VEGF and VEGFR expression in bronchial biopsy specimens. Demoly et al. (40) reasoned that VEGF "is a multifunctional cytokine which plays a role in chronic inflammation" and Hoshino et al. (92, 93) showed increased VEGF expression in CD34 cells, eosinophils, and macrophages. Asai et al. (7) showed increased VEGF sputum levels in asthmatic patients. Lee et al. (126) demonstrated that VEGF contributed to airway hyperreactivity in a murine model of toluene diisocyanate-induced asthma, and Kanazawa et al. (103) invoked a role of VEGF in exercise-induced asthma. It has been shown that VEGF causes VEGFR-1-dependent eosinophil chemotaxis (7) and that mast cells produce VEGF; T lymphocytes possess both VEGFR-1 and VEGFR-2 (25, 103), and T helper 2 (Th2) cytokines (IL-4, IL-5, IL-13) enhance VEGF production in airway smooth muscle cells (34). Indeed, VEGF could play an important role in asthma, causing hypervascularity of the airways (93) and mucosa edema; after all, VEGF is a potent permeability factor. Interestingly, -adrenergic agonists increase the transcription of VEGF mRNA (58).

It is tempting to speculate that VEGF may play a role in the immune response in asthma (Th2 response and VEGF overexpression) and also in COPD/emphysema (Th1 response and decreased VEGF expression and impaired VEGFR signaling). If so, then asthma is associated with angiogenesis (93) and emphysema with impaired vessel maintenance (199). A "VEGF-centric" vascular hypothesis of chronic airway diseases would transcend current concepts of the pathobiology of asthma and COPD, introducing a link between VEGF and T cells, hypervascularity (angiogenesis), Th2 predominant chronic inflammation on one side, and emphysema, loss of alveolar septal capillaries, and a Th1 response on the other side of a spectrum of presentations.

	LUNG CANCER

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
VEGF is overexposed in malignant tumors (10), including glioblastoma multiforme, and in lung cancer (110, 146). Recently, it had been appreciated that VEGF-C and VEGFR-3 are expressed in gastric and lung cancer tissues and that these proteins may be important as drivers of tumor lymphangiogenesis (150). Kaya and associates (110) reported that high serum VEGF levels in patients with lung cancer are associated with a poor prognosis. However, a meta-analysis by Nieder et al. (146) failed to confirm this finding, yet lung cancer macrophage VEGF-C expression correlated with the prognosis, and high tumor vascularity was associated with high VEGF and E-cadherin expression and low tumor cell differentiation (170). VGA1102, a novel VEGFR antagonist, has been shown to inhibit the growth of LC-6 human non-small cell lung cancer cells (193), and likewise AEE788, a combined EGF and VEGFR antagonist, inhibited VEGF-induced angiogenesis in tumor-bearing mice (185). Tumor-infiltrating T cells express VEGF (59, 132), suggesting that they can play a role in tumor vessel growth, and, in addition to chronic lymphocytic leukemia cells, autocrine VEGF may, via STAT proteins, enhance the resistance of these cells to apoptosis (50, 127).

	SYNOPSIS

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 
In the adult lung, VEGF is homeostatic, part of the "lung structure maintenance program," which, to play its pleiotropic regulatory roles, must be at the right place in the right amount (174). Too much VEGF production and action may lead to pleural effusion (26) and contribute to the increased vascular permeability (159) in acute lung injury (106, 144).

Whereas VEGF as well as VEGFR-1 and VEGFR-2 proteins are highly overexpressed in the fibromyxoid lesions in bronchiolitis obliterans (119), Cosgrove et al. (35) showed lack of vasculature in the myofibroblastic foci associated with lack of VEGF expression in idiopathic pulmonary fibrosis, and administration of VEGF to immunosuppressed allografts improved the rate and density of allograft reepithelialization (74).

This pleiotrophic angiogenesis and endothelial cell survival factor is of critical importance for lung development and postnatal lung tissue maturation (15, 39, 134) and plays a role in the pathogenesis of COPD/emphysema, acute lung injury, asthma, severe angioproliferative pulmonary hypertension, and in lung cancer. New data (Gebb S, Tuder RM, Voelkel NF, Abman SH, unpublished observations) demonstrated arrested branching morphogenesis in the rat fetal lung explant preparation within 24 h after addition of the combined VEGFR-1 and VEGFR-2 antagonist SU-5416; interestingly, not only was there a loss of vasculature, as shown by loss of eNOS staining, but a dose-dependent reduction in VEGFR-2 mRNA, shown by in situ hybridization and disappearance of VEFGR-2 (KDR) protein by Western blotting (Gebb S, Tuder RM, Voelkel NF, Abman SH, unpublished observations). This study not only illustrates the developmentally important role of VEGF but also the complex relationship between VEGFR signaling and receptor expression.

In addition to the control of angiogenesis and tumor angiogenesis, it is now becoming clear that VEGFRs are involved in macrophage functions, for example, in the phagocytic uptake of apoptotic cells (83), and also that VEGF and VEGFRs may play a major role in immune surveillance and immune modulation (125). Lack of VEGFR signals causes loss of vasculature, even in skeletal muscles (175), whereas hyperactive VEGFR signaling causes angioproliferation (86). However, as VEGFR antagonists inhibit endothelial cell growth tissue dependently, paradoxically, induction of initial endothelial cell apoptosis may be followed by the evolution of apoptosis-resistant cells and subsequent hyperproliferation of these surviving endothelial cells (161).

Organ-specific endothelial cells (65) differ in their capacity to generate VEGF protein for their own (autocrine) survival and maintenance and, therefore, may depend, to varying degrees, on contextual epithelial cell and inflammatory cell VEGF sources. The fact that lung microvascular endothelial cells produce and secrete large amounts of VEGF protein (171) may be teleologically explained, i.e., these cells produce so much VEGF because they "need" it for their survival. This might explain why lung microvascular endothelial cells are particularly vulnerable to VEGFR blockade and why VEGF is critical for the structural integrity of the lung.

It is probably not by accident that the regulation of production and stability of this important protein and its multiple signaling pathways are enormously complex, as is the transcriptional control and stability of the upstream transcription factor HIF-1 (173, 204). It is becoming clear that oxygen and oxidative stress are central in this fabric of regulatory mechanisms, since hypoxia also induces the expression of endoplasmatic reticulum oxidoreduction-1-L (137), which controls VEGF secretion, and oxidative stress inactivates VEGF survival signaling in endothelial cells via the action of peroxynitrite (46).

Further complexity has been added recently to the interaction between VEGF and prostacyclin. Neagoe et al. (145) showed that VEGF-induced prostacyclin synthesis by endothelial cells requires a VEGFR-1/VEGFR-2 heterodimer, and Buchanan et al. (17) demonstrated that prostacyclin-induced VEGF production was cyclooxygenase-2 dependent. Thus, it is likely that, also in the lung vessels, VEGF, prostacyclin, and NO are forever intricately linked and form the backbone of their biology (Fig. 2). Finally, since VEGF plays a critical role in the mobilization of precursor cells from the bone marrow (122), VEGF may well control precursor cell-dependent lung tissue repair and the number of bone marrow-derived mast cells, megacaryocytes, and dendritic cells in the lung.

	FOOTNOTES

 

Address for reprint requests and other correspondence: N. F. Voelkel, Division of Pulmonary Sciences and Critical Care Medicine, 4200 E. Ninth Ave., C272, Denver, CO 80262 (e-mail: norbert.voelkel{at}uchsc.edu)

	REFERENCES

TOP ABSTRACT BIOLOGICAL ACTIVITIES OF VEGF TRANSCRIPTIONAL CONTROL OF VEGF... PlGF VEGFRs VEGF-INDUCED CELL SIGNALING ROLE OF VEGF IN... PULMONARY HYPERTENSION LUNG INJURY EMPHYSEMA ASTHMA LUNG CANCER SYNOPSIS REFERENCES

 

1. Abid MR, Schoots IG, Spokes KC, Wu SQ, Mawhinney C, and Aird WC. Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and IB/NF-B. J Biol Chem 279: 44030–44038, 2004.[Abstract/Free Full Text]
2. Ahmed A, Dearn S, Shams M, Li XF, Sangha RK, Rola-Pleszczynski M, and Jiang J. Localization, quantification, and activation of platelet-activating factor receptor in human endometrium during the menstrual cycle: PAF stimulates NO, VEGF, and FAKpp125. FASEB J 12: 831–843, 1998.[Abstract/Free Full Text]
3. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, and Dimmeler S. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9: 1370–1376, 2003.[CrossRef][Web of Science][Medline]
4. Akeson AL, Greenberg JM, Cameron JE, Thompson FY, Brooks SK, Wiginton D, and Whitsett JA. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Dev Biol 264: 443–455, 2003.[CrossRef][Web of Science][Medline]
5. Alon T, Hemo I, Itin A, Pe'er J, Stone J, and Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1: 1024–1028, 1995.[CrossRef][Web of Science][Medline]
6. Arcot SS, Lipke DW, Gillespie MN, and Olson JW. Alterations of growth factor transcripts in rat lungs during development of monocrotaline-induced pulmonary hypertension. Biochem Pharmacol 46: 1086–1091, 1993.[CrossRef][Web of Science][Medline]
7. Asai K, Kanazawa H, Kamoi H, Shiraishi S, Hirata K, and Yoshikawa J. Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients. Clin Exp Allergy 33: 595–599, 2003.[CrossRef][Web of Science][Medline]
8. Asikainen TM, Ahmad A, Schneider BK, Ho WB, Arend M, Brenner M, Gunzler V, and White CW. Stimulation of HIF-1, HIF-2, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med 38: 1002–1013, 2005.[CrossRef][Web of Science][Medline]
9. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, and Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9: 936–943, 2003.[CrossRef][Web of Science][Medline]
10. Bando H, Brokelmann M, Toi M, Alitalo K, Sleeman JP, Sipos B, Grone HJ, and Weich HA. Immunodetection and quantification of vascular endothelial growth factor receptor-3 in human malignant tumor tissues. Int J Cancer 111: 184–191, 2004.[CrossRef][Web of Science][Medline]
11. Barleon B, Reusch P, Totzke F, Herzog C, Keck C, Martiny-Baron G, and Marme D. Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors. Angiogenesis 4: 143–154, 2001.[CrossRef][Medline]
12. Benjamin LE, Hemo I, and Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125: 1591–1598, 1998.[Abstract]
13. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, and Maniscalco WM. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 164: 1971–1980, 2001.[Abstract/Free Full Text]
14. Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, and Hutchinson IV. Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene. Hum Immunol 60: 1245–1249, 1999.[CrossRef][Web of Science][Medline]
15. Brown KR, England KM, Goss KL, Snyder JM, and Acarregui MJ. VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281: L1001–L1010, 2001.[Abstract/Free Full Text]
16. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, and Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor-2 protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia, J Clin Invest 111: 1519–1527, 2003.[CrossRef][Web of Science][Medline]
17. Buchanan FG, Chang W, Sheng H, Shao J, Morrow JD, and DuBois RN. Up-regulation of the enzymes involved in prostacyclin synthesis via Ras induces vascular endothelial growth factor. Gastroenterology 127: 1391–1400, 2004.[CrossRef][Web of Science][Medline]
18. Campbell AI, Zhao Y, Sandhu R, and Stewart DJ. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104: 2242–2248, 2001.[Abstract/Free Full Text]
19. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, and Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318–1321, 1998.[Abstract/Free Full Text]
20. Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, Ehler E, Kakkar VV, Stalmans I, Mattot V, Perriard JC, Dewerchin M, Flameng W, Nagy A, Lupu F, Moons L, Collen D, D'Amore PA, and Shima DT. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5: 495–502, 1999.[CrossRef][Web of Science][Medline]
21. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De MM, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, and Persico MG. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7: 575–583, 2001.[CrossRef][Web of Science][Medline]
22. Casella I, Feccia T, Chelucci C, Samoggia P, Castelli G, Guerriero R, Parolini I, Petrucci E, Pelosi E, Morsilli O, Gabbianelli M, Testa U, and Peschle C. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood 101: 1316–1323, 2003.[Abstract/Free Full Text]
23. Chai J, Jones MK, and Tarnawski AS. Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis. FASEB J 18: 1264–1266, 2004.[Abstract/Free Full Text]
24. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, and Schumacker PT. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1 during hypoxia: a mechanism of O₂ sensing. J Biol Chem 275: 25130–25138, 2000.[Abstract/Free Full Text]
25. Chen WS, Kitson RP, and Goldfarb RH. Modulation of human NK cell lines by vascular endothelial growth factor and receptor VEGFR-1 (FLT-1). In Vivo 16: 439–445, 2002.[Web of Science][Medline]
26. Cheng D, Rodriguez RM, Perkett EA, Rogers J, Bienvenu G, Lappalainen U, and Light RW. Vascular endothelial growth factor in pleural fluid. Chest 116: 760–765, 1999.[CrossRef][Web of Science][Medline]
27. Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Gera L, Tuder RM, and Voelkel NF. Methylprednisolone causes matrix metalloproteinase-dependent emphysema in adult rats. Am J Respir Crit Care Med 167: 1516–1521, 2003.[Abstract/Free Full Text]
28. Choi WI, Quinn DA, Park KM, Moufarrej RK, Jafari B, Syrkina O, Bonventre JV, and Hales CA. Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury. Am J Respir Crit Care Med 167: 1627–1632, 2003.[Abstract/Free Full Text]
29. Christou H, Yoshida A, Arthur V, Morita T, and Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 18: 768–776, 1998.[Abstract/Free Full Text]
30. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, and Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271: 17629–17634, 1996.[Abstract/Free Full Text]
31. Clerch LB, Baras AS, Massaro GD, Hoffman EP, and Massaro D. DNA microarray analysis of neonatal mouse lung connects regulation of KDR with dexamethasone-induced inhibition of alveolar formation. Am J Physiol Lung Cell Mol Physiol 286: L411–L419, 2004.[Abstract/Free Full Text]
32. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, and Carmeliet P. Loss of HIF-2 and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8: 702–710, 2002.[Web of Science][Medline]
33. Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, and Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 349: 1113–1122, 2003.[Abstract/Free Full Text]
34. Corne J, Chupp G, Lee CG, Homer RJ, Zhu Z, Chen Q, Ma B, Du Y, Roux F, McArdle J, Waxman AB, and Elias JA. IL-13 stimulates vascular endothelial cell growth factor and protects against hyperoxic acute lung injury. J Clin Invest 106: 783–791, 2000.[Web of Science][Medline]
35. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, and Worthen GS. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 170: 242–251, 2004.[Abstract/Free Full Text]
36. Cross MJ, Dixelius J, Matsumoto T and Claesson-Welsh L. VEGF-receptor signal transduction. Trends Biochem Sci 28: 488–494, 2003.[CrossRef][Web of Science][Medline]
37. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, and Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241, 1997.[CrossRef][Web of Science][Medline]
38. De Boer WI. Cytokines and therapy in COPD: a promising combination? Chest 121: 209S–218S, 2002.[CrossRef]
39. DeMello DE and Reid LM. Embryonic and early fetal development of human lung vasculature and its functional implications. Pediatr Dev Pathol 3: 439–449, 2000.[CrossRef][Web of Science][Medline]
40. Demoly P, Maly FE, Mautino G, Grad S, Gougat C, Sahla H, Godard P, and Bousquet J. VEGF levels in asthmatic airways do not correlate with plasma extravasation. Clin Exp Allergy 29: 1390–1394, 1999.[CrossRef][Web of Science][Medline]
41. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, and Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67: 737–744, 2000.[CrossRef][Web of Science][Medline]
42. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, and Carbone DP. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 174: 215–222, 2005.[Abstract/Free Full Text]
43. Dimmeler S and Zeiher AM. Nitric oxide—an endothelial cell survival factor. Cell Death Differ 6: 964–968, 1999.[CrossRef][Web of Science][Medline]
44. Duyndam MC, Hilhorst MC, Schluper HM, Verheul HM, van Diest PJ, Kraal G, Pinedo HM, and Boven E. Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts. Am J Pathol 160: 537–548, 2002.[Abstract/Free Full Text]
45. Edelman JL, Lutz D, and Castro MR. Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown. Exp Eye Res 80: 249–258, 2005.[CrossRef][Web of Science][Medline]
46. El-Remessy AB, Bartoli M, Platt DH, Fulton D, and Caldwell RB. Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration. J Cell Sci 118: 243–252, 2005.[Abstract/Free Full Text]
47. Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, and Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4: 915–924, 1999.[CrossRef][Web of Science][Medline]
48. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, and Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-, PGE₂, and PAF. J Clin Invest 101: 890–898, 1998.[Web of Science][Medline]
49. Fadok VA, de Cathelineau A, Daleke DL, Henson PM, and Bratton DL. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J Biol Chem 276: 1071–1077, 2001.[Abstract/Free Full Text]
50. Farahani M, Treweeke AT, Toh CH, Till KJ, Harris RJ, Cawley JC, Zuzel M, and Chen H. Autocrine VEGF mediates the antiapoptotic effect of C.D154 on CLL cells. Leukemia 19: 524–530, 2005.[Web of Science][Medline]
51. Fehrenbach H, Haase M, Kasper M, Koslowski R, Schuh D, and Muller M. Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis. Virchows Arch 435: 20–31, 1999.[CrossRef][Web of Science][Medline]
52. Feistritzer C, Kaneider NC, Sturn DH, Mosheimer BA, Kahler CM, and Wiedermann CJ. Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. Am J Respir Cell Mol Biol 30: 729–735, 2004.[Abstract/Free Full Text]
53. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, and Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1 and insulin-like growth factor 2. Cancer Res 59: 3915–3918, 1999.[Abstract/Free Full Text]
54. Ferrara N and Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161: 851–858, 1989.[CrossRef][Web of Science][Medline]
55. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25: 581–611, 2004.[Abstract/Free Full Text]
56. Ferrara N, Hillan KJ, Gerber HP, and Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3: 391–400, 2004.[CrossRef][Web of Science][Medline]
57. Fong GH, Rossant J, Gertsenstein M, and Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376: 66–70, 1995.[CrossRef][Medline]
58. Fredriksson JM, Lindquist JM, Bronnikov GE, and Nedergaard J. Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a -adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. J Biol Chem 275: 13802–13811, 2000.[Abstract/Free Full Text]
59. Freeman MR, Schneck FX, Gagnon ML, Corless C, Soker S, Niknejad K, Peoples GE, and Klagsbrun M. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res 55: 4140–4145, 1995.[Abstract/Free Full Text]
60. Fujio Y and Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 274: 16349–16354, 1999.[Abstract/Free Full Text]
61. Fujita M, Mason RJ, Cool C, Shannon JM, Hara N, and Fagan KA. Pulmonary hypertension in TNF--overexpressing mice is associated with decreased VEGF gene expression. J Appl Physiol 93: 2162–2170, 2002.[Abstract/Free Full Text]
62. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, and Jain RK. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA 98: 2604–2609, 2001.[Abstract/Free Full Text]
63. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, and Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5: 2963–2970, 1999.[Abstract/Free Full Text]
65. Gebb S and Stevens T. On lung endothelial cell heterogeneity. Microvasc Res 68: 1–12, 2004.[CrossRef][Web of Science][Medline]
66. Gebb SA and Shannon JM. Tissue interactions mediate early events in pulmonary vasculogenesis. Dev Dyn 217: 159–169, 2000.[CrossRef][Web of Science][Medline]
67. Geiger R, Berger RM, Hess J, Bogers AJ, Sharma HS, and Mooi WJ. Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J Pathol 191: 202–207, 2000.[CrossRef][Web of Science][Medline]
68. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, and Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273: 30336–30343, 1998.[Abstract/Free Full Text]
69. Gerber HP, Dixit V, and Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273: 13313–13316, 1998.[Abstract/Free Full Text]
70. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, and Ferrara N. VEGF is required for growth and survival in neonatal mice. Development 126: 1149–1159, 1999.[Abstract]
71. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, Hong K, Marsters JC, and Ferrara N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417: 954–958, 2002.[CrossRef][Medline]
72. Gnarra JR, Zhou S, Merrill MJ, Wagner JR, Krumm A, Papavassiliou E, Oldfield EH, Klausner RD, and Linehan WM. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 93: 10589–10594, 1996.[Abstract/Free Full Text]
73. Golpon HA, Fadok VA, Taraseviciene-Stewart L, Scerbavicius R, Sauer C, Welte T, Henson PM, and Voelkel NF. Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J 18: 1716–1718, 2004.[Abstract/Free Full Text]
74. Govindaraj S, Gordon R, and Genden EM. Effect of fibrin matrix and vascular endothelial growth factor on reepithelialization of orthotopic murine tracheal transplants. Ann Otol Rhinol Laryngol 113: 797–804, 2004.[Web of Science][Medline]
75. Grosskreutz CL, nand-Apte B, Duplaa C, Quinn TP, Terman BI, Zetter B, and D'Amore PA. Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res 58: 128–136, 1999.[CrossRef][Web of Science][Medline]
76. Grover TR, Parker TA, Zenge JP, Markham NE, Kinsella JP, and Abman SH. Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 284: L508–L517, 2003.[Abstract/Free Full Text]
77. Hamada N, Kuwano K, Yamada M, Hagimoto N, Hiasa K, Egashira K, Nakashima N, Maeyama T, Yoshimi M, and Nakanishi Y. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol 175: 1224–1231, 2005.[Abstract/Free Full Text]
78. Haslett C, Savill JS, Whyte MK, Stern M, Dransfield I, and Meagher LC. Granulocyte apoptosis and the control of inflammation. Philos Trans R Soc Lond B Biol Sci 345: 327–333, 1994.[Web of Science][Medline]
79. Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L, Crystal RG, Moore MA, and Rafii S. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 193: 1005–1014, 2001.[Abstract/Free Full Text]
80. Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, and Rafii S. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8: 841–849, 2002.[CrossRef][Web of Science][Medline]
81. He H, Venema VJ, Gu X, Venema RC, Marrero MB, and Caldwell RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274: 25130–25135, 1999.[Abstract/Free Full Text]
82. Healy AM, Morgenthau L, Zhu X, Farber HW, and Cardoso WV. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung. Dev Dyn 219: 341–352, 2000.[CrossRef][Web of Science][Medline]
83. Henson PM, Bratton DL, and Fadok VA. Apoptotic cell removal. Curr Biol 11: R795–R805, 2001.[CrossRef][Web of Science][Medline]
84. Hirose S, Hosoda Y, Furuya S, Otsuki T, and Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 50: 472–479, 2000.[CrossRef][Web of Science][Medline]
85. Hodge S, Hodge G, Scicchitano R, Reynolds PN, and Holmes M. Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 81: 289–296, 2003.[CrossRef][Medline]
86. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, and De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56: 549–580, 2004.[Abstract/Free Full Text]
87. Hoffmann PR, deCathelineau AM, Ogden CA, Leverrier Y, Bratton DL, Daleke DL, Ridley AJ, Fadok VA, and Henson PM. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155: 649–659, 2001.[Abstract/Free Full Text]
88. Hoffmann PR, Kench JA, Vondracek A, Kruk E, Daleke DL, Jordan M, Marrack P, Henson PM, and Fadok VA. Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo. J Immunol 174: 1393–1404, 2005.[Abstract/Free Full Text]
89. Hornig C, Behn T, Bartsch W, Yayon A, and Weich HA. Detection and quantification of complexed and free soluble human vascular endothelial growth factor receptor-1 (sVEGFR-1) by ELISA. J Immunol Methods 226: 169–177, 1999.[CrossRef][Web of Science][Medline]
90. Hornig C, Barleon B, Ahmad S, Vuorela P, Ahmed A, and Weich HA. Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest 80: 443–454, 2000.[Web of Science][Medline]
91. Hosford GE and Olson DM. Effects of hyperoxia on VEGF, its receptors, and HIF-2 in the newborn rat lung. Am J Physiol Lung Cell Mol Physiol 285: L161–L168, 2003.[Abstract/Free Full Text]
92. Hoshino M, Takahashi M, and Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol 107: 295–301, 2001.[CrossRef][Web of Science][Medline]
93. Hoshino M, Nakamura Y, and Hamid QA. Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma. J Allergy Clin Immunol 107: 1034–1038, 2001.[CrossRef][Web of Science][Medline]
94. Huynh ML, Fadok VA, and Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-1 secretion and the resolution of inflammation. J Clin Invest 109: 41–50, 2002.[CrossRef][Web of Science][Medline]
95. Hyder SM, Huang JC, Nawaz Z, Boettger-Tong H, Makela S, Chiappetta C, and Stancel GM. Regulation of vascular endothelial growth factor expression by estrogens and progestins. Environ Health Perspect 108, Suppl 5: 785–790, 2000.[Web of Science][Medline]
96. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, and Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 93: 10595–10599, 1996.[Abstract/Free Full Text]
97. Ishida A, Murray J, Saito Y, Kanthou C, Benzakour O, Shibuya M, and Wijelath ES. Expression of vascular endothelial growth factor receptors in smooth muscle cells. J Cell Physiol 188: 359–368, 2001.[CrossRef][Web of Science][Medline]
98. Jackson JR, Seed MP, Kircher CH, Willoughby DA, and Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 11: 457–465, 1997.[Abstract]
99. Jakeman LB, Winer J, Bennett GL, Altar CA, and Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89: 244–253, 1992.[Web of Science][Medline]
100. Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF, and Abman SH. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol 279: L600–L607, 2000.[Abstract/Free Full Text]
101. Josko J and Mazurek M. Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit 10: RA89–RA98, 2004.[Web of Science][Medline]
102. Jung YJ, Isaacs JS, Lee S, Trepel J, and Neckers L. IL-1-mediated up-regulation of HIF-1 via an NFB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J 17: 2115–2117, 2003.[Abstract/Free Full Text]
103. Kanazawa H, Hirata K, and Yoshikawa J. Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients. Thorax 57: 885–888, 2002.[Abstract/Free Full Text]
104. Kanazawa H, Asai K, Hirata K, and Yoshikawa J. Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Am J Med 114: 354–358, 2003.[CrossRef][Web of Science][Medline]
105. Kaneko Y, Kitazato K, and Basaki Y. Integrin-linked kinase regulates vascular morphogenesis induced by vascular endothelial growth factor. J Cell Sci 117: 407–415, 2004.[Abstract/Free Full Text]
106. Kaner RJ, Ladetto JV, Singh R, Fukuda N, Matthay MA, and Crystal RG. Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Respir Cell Mol Biol 22: 657–664, 2000.[Abstract/Free Full Text]
107. Kariyazono H, Ohno T, Khajoee V, Ihara K, Kusuhara K, Kinukawa N, Mizuno Y, and Hara T. Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease. Pediatr Res 56: 953–959, 2004.[CrossRef][Web of Science][Medline]
108. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, and Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 106: 1311–1319, 2000.[Web of Science][Medline]
109. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, and Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 163: 737–744, 2001.[Abstract/Free Full Text]
110. Kaya A, Ciledag A, Gulbay BE, Poyraz BM, Celik G, Sen E, Savas H, and Savas I. The prognostic significance of vascular endothelial growth factor levels in sera of non-small cell lung cancer patients. Respir Med 98: 632–636, 2004.[CrossRef][Web of Science][Medline]
111. Kearney JB, Ambler CA, Monaco KA, Johnson N, Rapoport RG, and Bautch VL. Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division. Blood 99: 2397–2407, 2002.[Abstract/Free Full Text]
112. Kendall RL and Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90: 10705–10709, 1993.[Abstract/Free Full Text]
113. Kim H, Kim YN, Kim H, and Kim CW. Oxidative stress attenuates Fas-mediated apoptosis in Jurkat T cell line through Bfl-1 induction. Oncogene 24: 1252–1261, 2005.[CrossRef][Web of Science][Medline]
114. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, and Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-B activation in endothelial cells. J Biol Chem 276: 7614–7620, 2001.[Abstract/Free Full Text]
115. Klekamp JG, Jarzecka K, and Perkett EA. Exposure to hyperoxia decreases the expression of vascular endothelial growth factor and its receptors in adult rat lungs. Am J Pathol 154: 823–831, 1999.[Abstract/Free Full Text]
116. Koyama S, Sato E, Haniuda M, Numanami H, Nagai S, and Izumi T. Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Am J Respir Crit Care Med 166: 382–385, 2002.[Abstract/Free Full Text]
117. Ku DD, Zaleski JK, Liu S, and Brock TA. Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol Heart Circ Physiol 265: H586–H592, 1993.[Abstract/Free Full Text]
118. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE III, Nichols WC, and Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF- receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26: 81–84, 2000.[CrossRef][Web of Science][Medline]
119. Lappi-Blanco E, Soini Y, Kinnula V, and Paakko P. VEGF and bFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia. J Pathol 196: 220–227, 2002.[CrossRef][Web of Science][Medline]
120. Lassus P, Ristimaki A, Ylikorkala O, Viinikka L, and Andersson S. Vascular endothelial growth factor in human preterm lung. Am J Respir Crit Care Med 159: 1429–1433, 1999.[Abstract/Free Full Text]
121. Lassus P, Turanlahti M, Heikkila P, Andersson LC, Nupponen I, Sarnesto A, and Andersson S. Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 164: 1981–1987, 2001.[Abstract/Free Full Text]
122. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, and Nickenig G. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109: 220–226, 2004.[Abstract/Free Full Text]
123. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, and Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol Lung Cell Mol Physiol 283: L555–L562, 2002.[Abstract/Free Full Text]
124. Le Cras TD, Spitzmiller RE, Albertine KH, Greenberg JM, Whitsett JA, and Akeson AL. VEGF causes pulmonary hemorrhage, hemosiderosis, and air space enlargement in neonatal mice. Am J Physiol Lung Cell Mol Physiol 287: L134–L142, 2004.[Abstract/Free Full Text]
125. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim YK, McDonald DM, and Elias JA. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 10: 1095–1103, 2004.[CrossRef][Web of Science][Medline]
126. Lee YC, Kwak YG, and Song CH. Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma. J Immunol 168: 3595–3600, 2002.[Abstract/Free Full Text]
127. Lee YK, Shanafelt TD, Bone ND, Strege AK, Jelinek DF, and Kay NE. VEGF receptors on chronic lymphocytic leukemia (C.LL) B cells interact with STAT 1 and 3: implication for apoptosis resistance. Leukemia 19: 513–523, 2005.[Web of Science][Medline]
128. Leenders W, Lubsen N, van AM, Clauss M, Deckers M, Lowik C, Breier G, Ruiter D, and de WR. Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/Flk-1 and Flt-1. Lab Invest 82: 473–481, 2002.[Web of Science][Medline]
129. Leverrier Y and Ridley AJ. Requirement for Rho GTPases and PI 3-kinases during apoptotic cell phagocytosis by macrophages. Curr Biol 11: 195–199, 2001.[CrossRef][Web of Science][Medline]
130. Long X, Burke KA, Bigsby RM, and Nephew KP. Effects of the xenoestrogen bisphenol A on expression of vascular endothelial growth factor (VEGF) in the rat. Exp Biol Med 226: 477–483, 2001.[Abstract/Free Full Text]
131. Louzier V, Raffestin B, Leroux A, Branellec D, Caillaud JM, Levame M, Eddahibi S, and Adnot S. Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 284: L926–L937, 2003.[Abstract/Free Full Text]
132. Lummen G, Blass-Kampmann S, Rubben H, Suhr J, and Otto T. Tumor-infiltrating lymphocytes express vascular endothelial growth factor in renal cell carcinomas. Onkologie 23: 458–462, 2000.[Medline]
133. Luttun A and Carmeliet P. Angiogenesis and lymphangiogenesis: highlights of the past year. Curr Opin Hematol 11: 262–271, 2004.[CrossRef][Web of Science][Medline]
134. Maeda S, Suzuki S, Suzuki T, Endo M, Moriya T, Chida M, Kondo T, and Sasano H. Analysis of intrapulmonary vessels and epithelial-endothelial interactions in the human developing lung. Lab Invest 82: 293–301, 2002.[Web of Science][Medline]
135. Maniscalco WM, Watkins RH, D'Angio CT, and Ryan RM. Hyperoxic injury decreases alveolar epithelial cell expression of vascular endothelial growth factor (VEGF) in neonatal rabbit lung. Am J Respir Cell Mol Biol 16: 557–567, 1997.[Abstract]
136. Marrony S, Bassilana F, Seuwen K, and Keller H. Bone morphogenetic protein 2 induces placental growth factor in mesenchymal stem cells. Bone 33: 426–433, 2003.[Medline]
137. May D, Itin A, Gal O, Kalinski H, Feinstein E, and Keshet E. Ero1-L plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene 24: 1011–1020, 2005.[CrossRef][Web of Science][Medline]
138. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, and Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658, 2003.[CrossRef][Web of Science][Medline]
139. Medford AR, Keen LJ, Bidwell JL, and Millar AB. Vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome. Thorax 60: 244–248, 2005.[Abstract/Free Full Text]
140. Mezquita P, Parghi SS, Brandvold KA, and Ruddell A. Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation. Oncogene 24: 889–901, 2005.[CrossRef][Web of Science][Medline]
141. Morimoto K, Amano H, Sonoda F, Baba M, Senba M, Yoshimine H, Yamamoto H, Ii T, Oishi K, and Nagatake T. Alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice. Am J Respir Cell Mol Biol 24: 608–615, 2001.[Abstract/Free Full Text]
142. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, and Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors and . Proc Natl Acad Sci USA 97: 10972–10977, 2000.[Abstract/Free Full Text]
143. Munshi N, Fernandis AZ, Cherla RP, Park IW, and Ganju RK. Lipopolysaccharide-induced apoptosis of endothelial cells and its inhibition by vascular endothelial growth factor. J Immunol 168: 5860–5866, 2002.[Abstract/Free Full Text]
144. Mura M, dos Santos CC, Stewart D, and Liu M. Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol 97: 1605–1617, 2004.[Abstract/Free Full Text]
145. Neagoe PE, Lemieux C, and Sirois MG. Vascular endothelial growth factor (VEGF)-A165-induced prostacyclin synthesis requires the activation of VEGF receptor-1 and -2 heterodimer. J Biol Chem 280: 9904–9912, 2005.[Abstract/Free Full Text]
146. Nieder C, Andratschke N, Jeremic B, and Molls M. Comparison of serum growth factors and tumor markers as prognostic factors for survival in non-small cell lung cancer. Anticancer Res 23: 5117–5123, 2003.[Web of Science][Medline]
147. Niimi H, Arimura K, Jonosono M, Hashiguchi T, Kawabata M, Osame M, and Kitajima I. VEGF is causative for pulmonary hypertension in a patient with Crow-Fukase (POEMS) syndrome. Intern Med 39: 1101–1104, 2000.[Web of Science][Medline]
148. Norrby K. Mast cells and angiogenesis. APMIS 110: 355–371, 2002.[CrossRef][Web of Science][Medline]
149. Odaka C, Mizuochi T, Yang J, and Ding A. Murine macrophages produce secretory leukocyte protease inhibitor during clearance of apoptotic cells: implications for resolution of the inflammatory response. J Immunol 171: 1507–1514, 2003.[Abstract/Free Full Text]
150. Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H, and Tanaka F. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer 91: 498–503, 2004.[CrossRef][Web of Science][Medline]
151. Park JE, Keller GA, and Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4: 1317–1326, 1993.[Abstract]
152. Parker TA and Abman SH. The pulmonary circulation in bronchopulmonary dysplasia. Semin Neonatol 8: 51–61, 2003.[CrossRef][Medline]
153. Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M, Dreyfus P, Raffestin B, and Frelin C. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 275: H1948–H1956, 1998.[Abstract/Free Full Text]
154. Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, Lemarchand P, and Eddahibi S. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 23: 762–771, 2000.[Abstract/Free Full Text]
155. Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee ME, and Haber E. Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor- in cultured human vascular endothelial cells. J Clin Invest 98: 490–496, 1996.[Web of Science][Medline]
156. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, and Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor- in fibroblastic and epithelial cells. J Biol Chem 269: 6271–6274, 1994.[Abstract/Free Full Text]
157. Raoul W, Chailley-Heu B, Barlier-Mur AM, Delacourt C, Maitre B, and Bourbon JR. Effects of vascular endothelial growth factor on isolated fetal alveolar type II cells. Am J Physiol Lung Cell Mol Physiol 286: L1293–L1301, 2004.[Abstract/Free Full Text]
158. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, and Isner JM. Age-dependent impairment of angiogenesis. Circulation 99: 111–120, 1999.[Abstract/Free Full Text]
159. Roberts WG and Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108: 2369–2379, 1995.[Abstract]
160. Sakao S, Tatsumi K, Hashimoto T, Igari H, Shino Y, Shirasawa H, and Kuriyama T. Vascular endothelial growth factor and the risk of smoking-related COPD. Chest 124: 323–327, 2003.[CrossRef][Medline]
161. Sakao S, Taraceviciene-Stewart L, Lee JD, Wood K, Cool C, and Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J 19: 1178–1180, 2005.[Abstract/Free Full Text]
162. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732, 2003.[CrossRef][Web of Science][Medline]
163. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, and Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985, 1983.[Abstract/Free Full Text]
164. Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV, and Harden PN. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13: 260–264, 2002.[Abstract/Free Full Text]
165. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, and Schuh AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62–66, 1995.[CrossRef][Medline]
166. Shapiro SD. Vascular atrophy and VEGFR-2 signaling: old theories of pulmonary emphysema meet new data. J Clin Invest 106: 1309–1310, 2000.[Web of Science][Medline]
167. Shehata SM, Mooi WJ, Okazaki T, El Banna I, Sharma HS, and Tibboel D. Enhanced expression of vascular endothelial growth factor in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension. Thorax 54: 427–431, 1999.[Abstract/Free Full Text]
168. Shweiki D, Itin A, Soffer D, and Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845, 1992.[CrossRef][Medline]
169. Skurk C, Maatz H, Rocnik E, Bialik A, Force T, and Walsh K. Glycogen-synthase kinase3/-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells. Circ Res 96: 308–318, 2005.[Abstract/Free Full Text]
170. Stefanou D, Goussia AC, Arkoumani E, and Agnantis NJ. Expression of vascular endothelial growth factor and the adhesion molecule E-cadherin in non-small cell lung cancer. Anticancer Res 23: 4715–4720, 2003.[Web of Science][Medline]
171. Stevens T, Kasper M, Cool C, and Voelkel NF. Pulmonary Circulation and Pulmonary Hypertension. In: Endothelial in Health and Disease, edited by Aird WC. Dekker, 2005, p. 417–437.
172. Stolk J, Rossie W, and Dijkman JH. Apocynin improves the efficacy of secretory leukocyte protease inhibitor in experimental emphysema. Am J Respir Crit Care Med 150: 1628–1631, 1994.[Abstract]
173. Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, and Candinas D. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J 15: 2445–2453, 2001.[Abstract/Free Full Text]
174. Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, Dvorak AM, and Dvorak HF. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol 158: 1145–1160, 2001.[Abstract/Free Full Text]
175. Tang K, Breen EC, Gerber HP, Ferrara NM, and Wagner PD. Capillary regression in vascular endothelial growth factor-deficient skeletal muscle. Physiol Genomics 18: 63–69, 2004.[Abstract/Free Full Text]
176. Tang K, Rossiter HB, Wagner PD, and Breen EC. Lung-targeted VEGF inactivation leads to emphysema phenotype in mice. J Appl Physiol 97: 1559–1566, 2004.[Abstract/Free Full Text]
178. Taraseviciene-Stewart L, Gera L, Hirth P, Voelkel NF, Tuder RM, and Stewart JM. A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model. Can J Physiol Pharmacol 80: 269–274, 2002.[CrossRef][Web of Science][Medline]
179. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Moore M, Sullivan A, Nicolls MR, Fontenot AP, Tuder RM, and Voelkel NF. An animal model of autoimmune emphysema. Am J Respir Crit Care Med 171: 734–742, 2005.[Abstract/Free Full Text]
180. Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, and Noble PW. Resolution of lung inflammation by CD44. Science 296: 155–158, 2002.[Abstract/Free Full Text]
181. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, and Shows TB. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677–1683, 1991.[Web of Science][Medline]
182. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, and Bohlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187: 1579–1586, 1992.[CrossRef][Web of Science][Medline]
183. Thickett DR, Armstrong L, Christie SJ, and Millar AB. Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome. Am J Respir Crit Care Med 164: 1601–1605, 2001.[Abstract/Free Full Text]
184. Tosello-Trampont AC, Nakada-Tsukui K, and Ravichandran KS. Engulfment of apoptotic cells is negatively regulated by Rho-mediated signaling. J Biol Chem 278: 49911–49919, 2003.[Abstract/Free Full Text]
185. Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J, Meyer T, Tang C, Wartmann M, Wood J, and Caravatti G. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 64: 4931–4941, 2004.[Abstract/Free Full Text]
186. Tsao PN, Su YN, Li H, Huang PH, Chien CT, Lai YL, Lee CN, Chen CA, Cheng WF, Wei SC, Yu CJ, Hsieh FJ, and Hsu SM. Overexpression of placenta growth factor contributes to the pathogenesis of pulmonary emphysema. Am J Respir Crit Care Med 169: 505–511, 2004.[Abstract/Free Full Text]
187. Tsurumi Y, Murohara T, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, and Isner JM. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med 3: 879–886, 1997.[CrossRef][Web of Science][Medline]
188. Tuder R, Zhen LCCY, Taraseviciene-Stewart L, Kasahara Y, Salvemini D, Voekel NF, and Flores SC. Oxidative stress and apoptosis interact and cause emphysema due to VEGF receptor blockade. Am J Respir Cell Mol Biol 29: 88–97, 2003.[Abstract/Free Full Text]
189. Tuder RM, Flook BE, and Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 95: 1798–1807, 1995.[Web of Science][Medline]
190. Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, Cool CD, Bishop AE, Geraci M, Semenza GL, Yacoub M, Polak JM, and Voelkel NF. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 195: 367–374, 2001.[CrossRef][Web of Science][Medline]
191. Tuder RM, Yeager ME, Geraci M, Golpon HA, and Voelkel NF. Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene. Eur Respir J 17: 1065–1069, 2001.[Free Full Text]
192. Tuder RM, Petrache I, Elias JA, Voekel NF, and Henson P. Apoptosis and emphysema: the missing link. Am J Respir Cell Mol Biol 28: 551–554, 2003.[Free Full Text]
193. Ueda Y, Yamagishi T, Samata K, Ikeya H, Hirayama N, Okazaki T, Nishihara S, Arai K, Yamaguchi S, Shibuya M, Nakaike S, and Tanaka M. A novel low molecular weight VEGF receptor-binding antagonist, VGA1102, inhibits the function of VEGF and in vivo tumor growth. Cancer Chemother Pharmacol 54: 16–24, 2004.[CrossRef][Web of Science][Medline]
194. Van der FM, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, and Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock 23: 35–38, 2005.[CrossRef][Web of Science][Medline]
195. Vandivier RW, Fadok VA, Ogden CA, Hoffmann PR, Brain JD, Accurso FJ, Fisher JH, Greene KE, and Henson PM. Impaired clearance of apoptotic cells from cystic fibrosis airways. Chest 121: 89S, 2002.[CrossRef]
196. Vandivier RW, Fadok VA, Hoffmann PR, Bratton DL, Penvari C, Brown KK, Brain JD, Accurso FJ, and Henson PM. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 109: 661–670, 2002.[CrossRef][Web of Science][Medline]
197. Vandivier RW, Ogden CA, Fadok VA, Hoffmann PR, Brown KK, Botto M, Walport MJ, Fisher JH, Henson PM, and Greene KE. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol 169: 3978–3986, 2002.[Abstract/Free Full Text]
198. Voelkel NF and Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest 106: 733–738, 2000.[Web of Science][Medline]
199. Voelkel NF, Cool C, Taraseviene-Stewart L, Geraci MW, Yeager M, Bull T, Kasper M, and Tuder RM. Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit Care Med 30: S251–S256, 2002.[CrossRef][Web of Science][Medline]
200. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, and Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269: 26988–26995, 1994.[Abstract/Free Full Text]
201. Wang H and Keiser JA. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res 83: 832–840, 1998.[Web of Science][Medline]
202. Wanstall JC, Gambino A, Jeffery TK, Cahill MM, Bellomo D, Hayward NK, and Kay GF. Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension. Cardiovasc Res 55: 361–368, 2002.[Abstract/Free Full Text]
203. Wyllie AH, Kerr JF, and Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 68: 251–306, 1980.[Medline]
204. Xie K, Wei D, Shi Q, and Huang S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev 15: 297–324, 2004.[CrossRef][Web of Science][Medline]
205. Yamaguchi R, Yano H, Nakashima Y, Ogasawara S, Higaki K, Akiba J, Hicklin DJ, and Kojiro M. Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep 7: 725–729, 2000.[Web of Science][Medline]
206. Yeager ME, Halley GR, Golpon HA, Voelkel NF, and Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 88: E2–E11, 2001.[Web of Science][Medline]
207. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, and Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1. J Clin Invest 103: 691–696, 1999.[Web of Science][Medline]
208. Zaiman AL and Tuder RM. Hypoxia-sensitive transcription factors and growth factors. In: Hypoxic Pulmonary Vasoconstriction, edited by Yuan JXJ. Norwell, MA: Kluwer Academic, 2004, p. 437–447.
209. Zaitseva M, Yue DS, Katzenellenbogen JA, Rogers PA, and Gargett CE. Estrogen receptor- agonists promote angiogenesis in human myometrial microvascular endothelial cells. J Soc Gynecol Investig 11: 529–535, 2004.[CrossRef][Medline]
210. Zeng X, Wert SE, Federici R, Peters KG, and Whitsett JA. VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo. Dev Dyn 211: 215–227, 1998.[CrossRef][Web of Science][Medline]

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