Hypoxia Enhances Platelet-derived Growth Factor Signaling in the Pulmonary Vasculature by Down-Regulation of Protein Tyrosine Phosphatases

Rationale: Platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of pulmonary hypertension (PH) because it promotes pulmonary vascular remodeling. PH is frequently associated with pulmonary hypoxia. Objectives: To investigate whether hypoxia alters PDGF beta receptor (beta PDGFR) signaling in the pulmonary vasculature. Methods: The impact of chronic hypoxia on signal transduction by the beta PDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo Measurements and Main Results: Chronic hypoxia significantly enhanced PDGF-BB-dependent proliferation and chemotaxis of hPASMC. Pharmacologic inhibition of PI3 kinase (PI3K) and PLC gamma abrogated these events under both normoxia and hypoxia. Although hypoxia did not affect beta PDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLC gamma (Y1021). The activated beta PDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Interestingly, hypoxia decreased expression of numerous PTPs (T cell PTP, density-enhanced phosphatase-1, PTP1B, and SH2 domain-containing phosphatase-2), resulting in reduced PTP activity. Hypoxia-inducible factor (HIF)-1 alpha is involved in this regulation of gene expression, because hypoxia-induced beta PDGFR hyperphosphorylation and PTP down-regulation were abolished by HIF-1 alpha siRNA and by the HIF-1 alpha inhibitor 2-methoxyestradiol. beta PDGFR hyperphosphorylation and PTP down-regulation were also present in vivo in mice with chronic hypoxia-induced PH. Conclusions: Hypoxia reduces expression and activity of beta PDGFR-antagonizing PTPs in a HIF-1 alpha-dependent manner, thereby enhancing receptor activation and proliferation and chemotaxis of hPASMC. Because hyperphosphorylation of the beta PDGFR and down-regulation of PTPs occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other hypoxia-associated diseases.