Abstract 18138: Endothelial PHD2 Loss Causes Pulmonary Arterial Hypertension via HIF-2 (Best of Basic Science Abstract)

Background: Key mediators of cellular adaption to hypoxia are hypoxia-inducible factor (HIF)-1 and -2, which are regulated by the prolyl hydroxylases (PHDs). Although the HIF pathway has been shown to be involved in the pathogenesis of pulmonary arterial hypertension (PAH), little is known about the cell type-specific functions of the PHD/HIF axis in this context. Here, we used a genetic approach to specifically dissect the contribution of the endothelial PHD/HIF axis in PAH. Methods: Endothelial cell specific HIF activation was achieved by crossing Vecadherin (Cdh5)-Cre transgenics to Phd2 floxed mice (ePHD2), while the contribution of each HIF isoform was assessed by generating double mutants lacking PHD2 and HIF-2 (ePHD2HIF2) or PHD2 and HIF-1 (PHD2HIF1). Right ventricular systolic pressure (RVSP) was directly measured via insertion of a 1.4F Mikro-tip catheter transducer into a surgically exposed right internal jugular vein. Results: Mice deficient for endothelial PHD2 showed significant activation of...