Abstract 5774: Hypoxia Enhances Platelet-derived Growth Factor Signaling in the Pulmonary Vasculature by HIF-1α-dependent Downregulation of Protein Tyrosine Phosphatases
Background: Platelet-derived growth factor (PDGF) plays a critical role in the development of pulmonary hypertension (PH) as it promotes pulmonary vascular remodeling. PH is frequently associated with severe pulmonary hypoxia. Here we investigated whether hypoxia alters PDGF β receptor (β PDGFR) signaling.
Methods and Results: Chronic hypoxia enhanced PDGF-BB-dependent proliferation and chemotaxis of human pulmonary arterial smooth muscle cells (hPASMC). Pharmacological inhibition of PI3 kinase (PI3K) and PLCγ abrogated these events both under normoxia and hypoxia. While hypoxia did not affect βPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at the binding sites for PI3K (Y751) and PLCγ (Y1021). The activated βPDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Strikingly, hypoxia decreased the expression of numerous PTPs (TC-PTP, DEP-1, PTP1B, SHP-2), resulting in reduced PTP activity. Putative hypoxia-inducible factor (HIF)-1α binding sites were identified in the promoter regions of the downregulated PTPs, and hypoxia-induced βPDGFR hyperphosphorylation and PTP downregulation were abolished by HIF-1α siRNA and by the HIF-1α inhibitor 2-methoxyestradiol. Immunohistochemistry and quantitative RT-PCR demonstrated that βPDGFR hyperphosphorylation and PTP downregulation were also present in vivo in mice with chronic hypoxia-induced PH.
Conclusions: Hypoxia reduces the expression and activity of βPDGFR-antagonizing PTPs in a HIF-1α-dependent manner, thereby enhancing receptor activation and proliferation/chemotaxis of hPASMC. As hyperphosphorylation of the βPDGFR and downregulation of PTPs also occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other proliferative diseases.