Abstract 9804: Overexpression of Pericyte Hif2a Exacerbates Hypoxia Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated pulmonary pressures and right-sided heart failure. Excessive accumulation of mural cells including pericytes surrounding the pulmonary vascular wall is one of the key pathological features seen in PAH. Whether pericytes contribute to other mural cell lineage and the underlying mechanisms responsible for their behavior are still elusive. Hypothesis: To evaluate the novel role of HIF2α signaling in pericytes in the pathogenesis of PAH. Methods and Results: NG2-Cre-ER mice are used to generate pericyte selective HIF2α overexpression (HIF2α NG2-OE ) and HIF2α NG2-OE reporter mice (HIF2α NG2-OE tdT) via tamoxifen injection for cell lineage identification. Compared to control, HIF2α NG2-OE mice in chronic hypoxia have significantly higher right ventricular systolic pressure and right ventricular hypertrophy along with increased muscularization and a greater abundance of NG2 + cells surrounding microvessels. Cellular lineage staining on HIF2α NG2-OE tdT reporter mice in chronic hypoxia show that tdT + cells accumulate in muscularized arterioles and exhibit significantly high levels of HIF2α protein, which initiates vascular cell proliferation and recruitment of inflammatory cells. Moreover, HIF2a over-expressed human pericytes exhibit greater contractility, impaired capacity to establish endothelial-pericyte communications, and loss of vascular integrity. Importantly, the HIF2a-targeted inhibitor attenuates hypoxia-induced pulmonary hypertension. Conclusions: HIF2α signaling in pericytes is a key mediator that contributes to abnormal vascular remodeling. Targeting HIF2α could potentially decrease pericyte migration as well as reducing vascular remodeling, therefore, serve as a potential treatment for certain forms of PH.