Project Summary/Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an obliterative vasculopathy of the distal pulmonary circulation. Adverse structural remodeling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle, with annual mortality averaging 10%. Current therapies can improve symptoms and delay disease progression, but there is no cure. There is a critical need to develop new therapies that effectively halt and reverse the disease by targeting the cellular and molecular mechanisms underlying the pathophysiology of PAH. In Sox17 mutant PAH patients, we postulate that loss-of-function mutations in the Sox17 gene result in insufficient upregulation of Sox17 during normal reparative responses to vascular injury allowing increased RUNX1 signaling to drive aberrant angiogenesis. Thus, our central hypothesis is that loss of repression of Runx1 by endothelial SOX17 predisposes to the development of PAH through impaired arterial endothelial differentiation and aberrant angiogenesis. To test our hypothesis, we plan the following specific aims: Aim 1. Determine if endothelial SOX17 deficiency leads to higher susceptibility of developing PAH. Aim 2. Determine if SOX17/RUNX1 imbalance leads to impaired arterial differentiation and aberrant angiogenesis following SuHx-PH induction. Aim 3: Determine if Sox17 mutant PAH patient iPSC-derived ECs have impaired arterial differentiation and defective angiogenic capability.