Abstract 19126: Endothelial-specific Deletion of Prolyl Hydroxylase Domain Protein 2 (PHD2) Results in Severe Pulmonary Hypertension in Mice by Enhancing the HIF2alpha Signaling Pathway

Abstract

Rationale: Sustained pulmonary vasoconstriction and excessive vascular remodeling are major causes of elevated pulmonary vascular resistance which leads to increased pulmonary arterial pressure in patients with pulmonary hypertension. Hypoxic-inducible factor (HIF) and its upstream regulators have been linked to the hypoxia response in vascular remodeling and the development of pulmonary hypertension. In this study, we aimed at defining whether increased HIF1α and/or HIF2α, due to endothelial cell specific deletion of prolyl hydroxylase domain protein 2 (PHD2) under normoxic condition are involved in or required for the initiation and progression of pulmonary hypertension. Methods: PHD2, HIF1α and HIF2α conditional knockout mice were created. Right ventricle systolic pressures (RVSP), right ventricular hypertrophy by RV/(LV+S) ratios, and small pulmonary artery smooth muscle layer thickness were measured. Pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) were isolated from wild type (WT) or knockout (KO) mice, followed with cell-based assays. Results: We report here that mice with targeted deletion of PHD2 developed severe pulmonary hypertension under normoxic condition. Conditional and inducible deletion of HIF2α in endothelial cells, but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. HIF2α KO mice had significantly lower RVSP, RV/(LV+S) ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia compared to their WT mice. Conclusion: This work shows that the endothelium is responsible for the development of pulmonary hypertension and it demonstrates a crucial role of PHD2/HIF signaling for hypoxic response in pulmonary hypertension. These findings unveil temporally and spatially distinct functions for HIFs in the development of pulmonary hypertension.