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1 Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
2 Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: Mita.Das{at}uchsc.edu.
Activation of the 
-smooth muscle actin (-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 trans-differentiation of vascular fibroblasts into myofibroblasts and also to evaluate potential signaling mechanisms governing this process. We found that hypoxia significantly up-regulates -SMA protein levels in bovine pulmonary artery adventitial fibroblasts. Increased -SMA expression is controlled at the transcriptional level because the -SMA gene promoter activity, assayed via a luciferase reporter, was markedly increased in transfected fibroblasts exposed to hypoxia. Hypoxic induction of the -SMA gene was mimicked by over-expression of constitutively active Gi2 (i2Q205L), but not G16 (-16Q212L). Blockade of hypoxia-induced -SMA expression with pertussis toxin, a Gi antagonist, confirmed a role for Gi in the hypoxia-induced trans-differentiation process. JNK Inhibitor II and SB202190, but not U0126, also attenuated -SMA expression in hypoxic fibroblasts suggesting the importance of JNK in the differentiation process. Hypoxia-induced proliferation which occurred concomitantly with hypoxia-induced differentiation, was blocked by U0126 suggesting that proliferation and differentiation take place through simultaneously activated parallel signaling pathways. Neutralizing antibody against TGF-
1 blocked only 30% of the hypoxia-induced -SMA promoter activity. Taken together, our results suggest that hypoxia induces differentiation of vascular fibroblasts into myofibroblasts by up-regulating the expression of -SMA and this increase in -SMA level occurs through Gi and JNK dependent signaling pathways.
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