Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGF receptor-JNK1 signalling

Department of Pharmaceutical Sciences, University of Wyoming, Laramie, WY, USA.
Cardiovascular Research (Impact Factor: 5.94). 06/2012; 95(3):356-65. DOI: 10.1093/cvr/cvs194
Source: PubMed


Pulmonary hypertension (PH) is a devastating condition for which no disease-modifying therapies exist. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit a heightened replication index. Because elevated platelet-derived growth factor β receptor (PDGFβ-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGFβ-R contributes to fibroblast proliferation and adventitial remodelling in PH.
Newborn calves were exposed to either ambient air (P(B) = 640 mmHg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGFβ-R phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGFβ-R activation with PDGF-BB stimulated higher replication in Neo-PH cells compared with that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species generation and extracellular signal-regulated kinase1/2 activation in both cell populations; however, only Neo-PH cell division via PDGFβ-R activation displayed a unique dependence on c-Jun N-terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of the JNK pathway, and JNK1-targeted siRNA selectively blunted Neo-PH cell proliferation.
Our data strongly suggest that hypoxia-induced modified cells engage the PDGFβ-R-JNK1 axis to confer distinctively heightened proliferation and adventitial remodelling in PH.

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    • "We have previously found several signs of remodeling in pulmonary arteries from CH and CIH2x2 rats, including wall hypertrophy due to increased smooth muscle and adventitial cells [15, 16]. Adventitial NADPH oxidase has been described to be involved in pulmonary artery adventitial fibroblasts proliferation [39, 40] and seems to be a primary site of superoxide anion production in the vessel wall [41–43]. We found that chronic or intermittent hypoxia substantially increased adventitial cell number together with a larger percentage of NADPH-positive cells. "
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