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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 297/2/L238    most recent 90591.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Burke, D. L. Articles by Stenmark, K. R. PubMed PubMed Citation Articles by Burke, D. L. Articles by Stenmark, K. R.

Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment

¹Developmental Lung Biology and CVP Research, Department of Pediatrics and Medicine, University of Colorado Denver, and ²Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado

Submitted 1 December 2008 ; accepted in final form 11 May 2009

Recent studies demonstrate that sustained hypoxia induces the robust accumulation of leukocytes and mesenchymal progenitor cells in pulmonary arteries (PAs). Since the factors orchestrating hypoxia-induced vascular inflammation are not well-defined, the goal of this study was to identify mediators potentially responsible for recruitment to and retention and differentiation of circulating cells within the hypoxic PA. We analyzed mRNA expression of 44 different chemokine/chemokine receptor, cytokine, adhesion, and growth and differentiation genes in PAs obtained via laser capture microdissection in adjacent lung parenchyma and in systemic arteries by RT-PCR at several time points of hypoxic exposure (1, 7, and 28 days) in Wistar-Kyoto rats. Analysis of inflammatory cell accumulation and protein expression of selected genes was concomitantly assessed by immunochemistry. We found that hypoxia induced progressive accumulation of monocytes and dendritic cells in the vessel wall with few T cells and no B cells or neutrophils. Upregulation of stromal cell-derived factor-1 (SDF-1), VEGF, growth-related oncogene protein- (GRO-), C5, ICAM-1, osteopontin (OPN), and transforming growth factor-β (TGF-β) preceded mononuclear cell influx. With time, a more complex pattern of gene expression developed with persistent upregulation of adhesion molecules (ICAM-1, VCAM-1, and OPN) and monocyte/fibrocyte growth and differentiation factors (TGF-β, endothelin-1, and 5-lipoxygenase). On return to normoxia, expression of many genes (including SDF-1, monocyte chemoattractant protein-1, C5, ICAM-1, and TGF-β) rapidly returned to control levels, changes that preceded the disappearance of monocytes and reversal of vascular remodeling. In conclusion, sustained hypoxia leads to the development of a complex, PA-specific, proinflammatory microenvironment capable of promoting recruitment, retention, and differentiation of circulating monocytic cell populations that contribute to vascular remodeling.

vascular remodeling; cytokines; progenitor cells; inflammation; pulmonary hypertension

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