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Am J Physiol Cell Physiol 286: C416-C425, 2004. First published October 15, 2003; doi:10.1152/ajpcell.00169.2003
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VASCULAR BIOLOGY

Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts

Megan Short,1 Raphel A. Nemenoff,2 W. Michael Zawada,3 Kurt R. Stenmark,1 and Mita Das1

1Department of Pediatrics, Developmental Lung Biology Research Laboratories, 2Renal Division, and 3Department of Medicine, Division of Clinical Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Submitted 29 April 2003 ; accepted in final form 13 October 2003

Activation of the {alpha}-smooth muscle actin ({alpha}-SMA) gene during the conversion of fibroblasts into myofibroblasts is an essential feature of various fibrotic conditions. Microvascular compromise and thus local environmental hypoxia are important components of the fibrotic response. The present study was thus undertaken to test the hypothesis that hypoxia can induce transdifferentiation of vascular fibroblasts into myofibroblasts and also to evaluate potential signaling mechanisms governing this process. We found that hypoxia significantly upregulates {alpha}-SMA protein levels in bovine pulmonary artery adventitial fibroblasts. Increased {alpha}-SMA expression is controlled at the transcriptional level because the {alpha}-SMA gene promoter activity, assayed via a luciferase reporter, was markedly increased in transfected fibroblasts exposed to hypoxia. Hypoxic induction of the {alpha}-SMA gene was mimicked by overexpression of constitutively active G{alpha}i2 ({alpha}i2Q205L) but not G{alpha}16 ({alpha}-16Q212L). Blockade of hypoxia-induced {alpha}-SMA expression with pertussis toxin, a G{alpha}i antagonist, confirmed a role for G{alpha}i in the hypoxia-induced transdifferentiation process. c-Jun NH2-terminal kinase (JNK) inhibitor II and SB202190, but not U0126, also attenuated {alpha}-SMA expression in hypoxic fibroblasts, suggesting the importance of JNK in the differentiation process. Hypoxia-induced increase in bromodeoxyuridine incorporation, which occurred concomitantly with hypoxia-induced differentiation, was blocked by U0126, suggesting that DNA synthesis and {alpha}-SMA expression take place through simultaneously activated parallel signaling pathways. Neutralizing antibody against transforming growth factor-{beta}1 blocked only 30% of the hypoxia-induced {alpha}-SMA promoter activity. Taken together, our results suggest that hypoxia induces differentiation of vascular fibroblasts into myofibroblasts by upregulating the expression of {alpha}-SMA, and this increase in {alpha}-SMA level occurs through G{alpha}i- and JNK-dependent signaling pathways.

{alpha}-smooth muscle actin promoter activity; G{alpha}i; Gq; extracellular regulated kinase; c-Jun NH2-terminal kinase; bromodeoxyuridine incorporation; transforming growth factor-{beta}1


Address for reprint requests and other correspondence: M. Das, Dept. of Pediatrics, B131, Univ. of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262 (E-mail: Mita.Das{at}uchsc.edu).




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