| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Lung Biology Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada; and 2Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, The Netherlands
Submitted 19 May 2004 ; accepted in final form 14 September 2004
Recent investigations have suggested an active role for endothelial cells in organ development, including the lung. Herein, we investigated some of the molecular mechanisms underlying normal pulmonary vascular development and their influence on epithelial branching morphogenesis. Because the lung in utero develops in a relative hypoxic environment, we first investigated the influence of low oxygen on epithelial and vascular branching morphogenesis. Two transgenic mouse models, the C101-LacZ (epithelial-LacZ marker) and the Tie2-LacZ (endothelial-LacZ marker), were used. At embryonic day 11.5, primitive lung buds were dissected and cultured at either 20 or 3% oxygen. At 24-h intervals, epithelial and endothelial LacZ gene expression was visualized by X-galactosidase staining. The rate of branching of both tissue elements was increased in explants cultured at 3% oxygen compared with 20% oxygen. Low oxygen increased expression of VEGF, but not that of the VEGF receptor (Flk-1). Expression of two crucial epithelial branching factors, fibroblast growth factor-10 and bone morphogenetic protein-4, were not affected by low oxygen. Epithelial differentiation was maintained at low oxygen as shown by surfactant protein C in situ hybridization. To explore epithelial-vascular interactions, we inhibited vascular development with antisense oligonucleotides targeted against either hypoxia inducible factor-1
or VEGF. Epithelial branching morphogenesis in vitro was dramatically abrogated when pulmonary vascular development was inhibited. Collectively, the in vitro data show that a low-oxygen environment enhances branching of both distal lung epithelium and vascular tissue and that pulmonary vascular development appears to be rate limiting for epithelial branching morphogenesis.
angiogenesis; vasculogenesis; airway branching; lung development
This article has been cited by other articles:
|
|
 |
|
  K. Ahlbrecht, J. Schmitz, U. Seay, C. Schwarz, R. Mittnacht-Kraus, A. Gaumann, R. V. Haberberger, S. Herold, G. Breier, F. Grimminger, et al. Spatiotemporal Expression of flk-1 in Pulmonary Epithelial Cells during Lung Development Am. J. Respir. Cell Mol. Biol., August 1, 2008; 39(2): 163 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Muehlethaler, A. M. Kunig, G. Seedorf, V. Balasubramaniam, and S. H. Abman Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L110 - L120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. White, K. J. Lavine, and D. M. Ornitz FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network Development, October 15, 2007; 134(20): 3743 - 3752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Groenman, M. Rutter, J. Wang, I. Caniggia, D. Tibboel, and M. Post Effect of chemical stabilizers of hypoxia-inducible factors on early lung development Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L557 - L567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Asikainen and C. W. White HIF stabilizing agents: shotgun or scalpel? Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L555 - L556. [Full Text] [PDF]
|
|
|
|
|
|
S. Wu, J. Peng, M. R. Duncan, K. Kasisomayajula, G. Grotendorst, and E. Bancalari ALK-5 Mediates Endogenous and TGF-beta1-Induced Expression of Connective Tissue Growth Factor in Embryonic Lung Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 552 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Groenman, M. Rutter, I. Caniggia, D. Tibboel, and M. Post Hypoxia-inducible Factors in the First Trimester Human Lung J. Histochem. Cytochem., April 1, 2007; 55(4): 355 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Asikainen, N. S. Waleh, B. K. Schneider, R. I. Clyman, and C. W. White Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L588 - L595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Balasubramaniam, A. M. Maxey, B. W. Fouty, and S. H. Abman Nitric oxide augments fetal pulmonary artery endothelial cell angiogenesis in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1111 - L1116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Zhang, O. W. Moe, J. A. Garcia, and C. C. W. Hsia Regulated expression of hypoxia-inducible factors during postnatal and postpneumonectomy lung growth Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L880 - L889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, R. Cade, and Z. Sun Human eNOS gene delivery attenuates cold-induced elevation of blood pressure in rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1161 - H1168. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
