Endothelial PHD2 in hypertensive vascular remodeling

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Summary: Arterial stiffness is the center feature of hypertension and has significant impact upon disease etiology and outcomes. So far, there is no cure for hypertensive arterial stiffness. Therefore, it is urgent to identify potential therapeutic targets that can reduce hypertensive arterial stiffness. Emerging evidence indicates that pericyte is a novel target of angiogenesis and vascular remodeling. Pericytes are a subpopulation of mesenchymal stem cells which can differentiate into osteoblasts, vascular smooth muscle cells (VSMCs) and fibroblasts. Pericytes promotes fibrosis formation via pericyte-(myo)-fibroblast transition (PFT). Pericyte also has been shown to differentiate into VSMCs at arterial remodeling zones in the heart. Our recent study found that deletion of oxygen sensor prolyl hydroxylase-2 (PHD2) in the endothelium resulted in excessive pericyte recruitment and arterial stiffness, and exacerbation of angiotensin II (Ang-II)-induced hypertension. Knockout of endothelial PHD2 caused an imbalanced arginase-2/eNOS favoring in arginase-2. Furthermore, knockout of endothelial PHD2 significantly increased osteogenic differentiation markers (SOX9, BMP2 and osteopontin) in the aorta and promoted VSMC calcification. Using NG2 pericyte tracing reporter NG2DsRedBAC mice, our preliminary study further suggested an important role of NG2+ pericyte in Ang-II mediating vascular remodeling. Based on our findings, we hypothesize that deactivation of PHD2 in EC enhances arterial stiffness and hypertension by the mechanisms involving an imbalanced arginase-2/eNOS and pericyte differentiation into VSMCs, osteogenic cells and fibroblasts via HIF-2α-PFKFB3 signaling pathway. Two specific aims will be proposed to test: Aim 1: To define the molecular mechanisms by which endothelial PHD2 regulates arterial stiffness with a focus on an imbalanced arginase-2/eNOS. We will determine: (i) whether deficiency of endothelial PHD2 induces an imbalanced arginase-2/eNOS via HIF-2α-PFKFB3 signaling pathway, (ii) whether pharmacologic blockade of HIF-2α using a clinic relevant and highly specific inhibitor PT2385 attenuates PFKFB3 expression, restores arginase-2/eNOS balances and reduces Ang-II-induced arterial stiffness in PHD2ECKO mice; and (3) whether knockout of arginase-2 reduces vascular remodeling and arterial stiffness in PHD2ECKO mice. Aim 2: To define the role of PHD2- PFKFB3 in mediating pericyte differentiation and hypertensive arterial stiffness. Using pericyte tracing reporter NG2DsRedBAC (Tg) mice crossing with PHD2ECKO mice, we will test whether inhibition of PFKFB3 attenuates osteogenic differentiation of pericytes, and reduces vascular calcification. We will further determine whether pharmacological activation of PHD2 or inhibition of PFKFB3 attenuates Ang- II-induced pericyte-fibroblast/VSMC transition, arterial stiffness and hypertensive vascular remodeling. Our study has clinical translational significance for the understanding of pericytes in vascular stiffness.