Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated pulmonary pressures and right ventricular (RV) failure. Inappropriate angiogenesis is a key pathological feature of PAH associated with endothelial dysfunction and progressive loss of pulmonary and RV microvessels. Angiogenesis is the process by which new vessels arise from existing vessels and is mainly driven by VEGF signaling. In response to VEGF-A, endothelial cells differentiate into tip cells, highly motile cells that direct vessel sprouting and elongation. Our previous R01 was built on the hypothesis that tip cell formation by PMVECs requires crosstalk between the VEGF and the Wnt/planar cell polarity (Wnt/PCP), a pathway responsible for coordinating cell movements during tissue morphogenesis. We demonstrated that Wnt/PCP activation in PMVECs is driven by the interaction between the ligand Wnt7a and ROR2, a tyrosine kinase receptor that phosphorylates residues in the endothelial VEGFR2 cytoplasmic domain to augment VEGF signaling output. We found that, compared to healthy donors, tip cell formation and angiogenesis in response to VEGF-A was significantly reduced in pulmonary microvascular endothelial cells (PMVEC) from PAH patients. Most importantly, supplementation with recombinant Wnt7a or restoration of ROR2 expression in PAH PMVECs results in recovery of the VEGF-A response, leading us to conclude that Wnt7a/ROR2 signaling is required for appropriate VEGF signaling activation and angiogenic response in PMVECs. This renewal will focus on elucidating the transcriptional and epigenetic mechanisms that regulate Wnt7a/ROR2 expression in healthy and PAH PMVECs (Aim 1), how interaction between ROR2 and integrins is required to establish a functional lung endothelial barrier (Aim 2), and the critical role of Wnt7a/ROR2 as a key pro- angiogenic mechanism that supports compensatory angiogenesis during RV adaptation to PAH (Aim 3). The studies in this renewal will confirm the role of Wnt7a/ROR2 signaling as a master regulator of cardiopulmonary angiogenesis and demonstrate the therapeutic potential of restoring Wnt7a/ROR2 signaling to prevent small vessel loss and improve RV function in PAH.