Endothelial-pericyte interactions in the pathogenesis of pulmonary arterial hypertension

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Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated pulmonary pressures and right heart failure. A hallmark of PAH pathology is progressive loss and inappropriate regeneration of pulmonary and right ventricular (RV) microvessels. Pericytes are highly specialized mural cells that interact with endothelial cells to provide structural support and facilitate vessel maturation during angiogenesis. Our studies show that inability to establish proper endothelial-pericyte (EC-PC) interactions is associated with pulmonary small vessel loss and insufficient angiogenesis in PAH, leading us to speculate that targeting the mechanisms that orchestrate EC-PC interactions could open new therapeutic opportunities for PAH. We have demonstrated that dysfunctional Wnt/planar cell polarity (PCP) signaling contributes to small vessel loss in PAH by disrupting lung EC-PC interactions. We found that pulmonary microvascular endothelial cells (PMVECs) release Wnt5a to recruit lung pericytes via ROR2-dependent Wnt/PCP activation in pericytes. Compared to healthy donors, both Wnt5a production and ROR2-dependent Wnt/PCP activation are significantly reduced in PAH PMVECs and pericytes, respectively. We also found that endothelial-specific Wnt5a deletion in mice was associated with decompensated RV failure characterized by disrupted EC-PC interactions and reduced RV capillary density. Based on our findings, we hypothesize that loss of Wnt/PCP signaling contributes to lung and RV vessel dysfunction in PAH by disrupting the establishment of EC-PC interactions and angiogenesis. In this renewal, we plan to: (Aim 1) Elucidate the mechanisms responsible for inappropriate Wnt5a expression by PAH PMVECs, (Aim 2) Elucidate the mechanisms responsible for dysfunctional ROR2 activity in PAH pericytes, and (Aim 3) Demonstrate that Wnt5a/ROR2 signaling plays a key role in RV remodeling and angiogenesis in response to PAH. Understanding how Wnt/PCP orchestrates endothelial-pericyte interactions will provide insight into the PAH pathogenesis and open new therapeutic opportunities to promote regeneration of lost vessels, prevent progression and improve clinical outcomes for patients afflicted with this devastating disease.