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WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension.
European Respiratory Journal 2023 April 7
INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.
METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).
RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.
CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.
METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).
RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.
CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.
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