Abstract 481: Regulatory Role Of Endothelial PHD2 On Hypertensive Arterial Stiffness And Vascular Calcification

Abstract

Arterial stiffness is the center feature of hypertension and has significant impact upon disease etiology and outcomes. Up to date, there is no therapy available to efficiently target arterial stiffness. Emerging evidence indicates that prolyl hydroxylase protein-2 (PHD2) is a novel target of vascular remodeling. Although endothelial PHD2 has been shown to contribute to pulmonary hypertension, the role of PHD2 on arterial stiffness and calcification remains elusive. Here, we investigated the underlying mechanisms of endothelial PHD2 on arterial stiffness and calcification. Using Doppler ultrasound to measure pulse-wave velocity (PWV), we found that PHD2 EC KO mice had a significant increase in arterial stiffness at 7 month old age. PWV was further increased in the PHD2 EC KO mice at 12 month old age, but this was not seen in the control mice. We then further tested whether PHD2 EC KO mice sensitized hypertension-induced arterial stiffness by infusion with angiotensin II for 4 weeks. Infusion of control mice with Ang-II resulted in a time-dependent increase in PWV. Ang-II-induced PWV was further elevated in the PHD2 EC KO mice. H&E staining showed that the aorta media thickness was significantly increased in the aorta of PHD2 EC KO mice. Infusion of mice with Ang-II for 4 weeks resulted in a significant increase in media thickness. The aorta media thickness was significantly increased in the aorta of PHD2 EC KO mice + Ang-II as compared to control mice + Ang II. Mechanistically, the arginase-2 expression and activity were significantly upregulated in the aorta of PHD2 EC KO mice. Deficiency of PHD2 in EC further promoted Ang-II-induced arginase activity. In addition, knockout of PHD2 in EC resulted in a five- fold increase in SOX9 expression in the mouse aorta as compared to PHD2 f/f (WT) control. Similarly, BMP2 expression was increased in the aorta of PHD2 EC KO mice. Co-staining of alkaline phosphatase (ALP) with BMP2 further showed an increased co-staining ALP/BMP2 in the aorta of PHD2 EC KO mice. Alizarin Red staining revealed a significant increase in area (%) of calcification in the aorta of PHD2 EC KO mice. Our study indicates a novel role of endothelial PHD2 in the regulation of arterial stiffness and calcification.