WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension
| Autor: | Ananya Chakraborty, Abinaya Nathan, Mark Orcholski, Stuti Agarwal, Elya A. Shamskhou, Natasha Auer, Ankita Mitra, Eleana Stephanie Guardado, Gowri Swaminathan, David F. Condon, Joyce Yu, Matthew McCarra, Nicholas H. Juul, Alden Mallory, Roberto A. Guzman-Hernandez, Ke Yuan, Vanesa Rojas, Joseph T. Crossno, Lai-Ming Yung, Paul B. Yu, Thomas Spencer, Robert A. Winn, Andrea Frump, Vijaya Karoor, Tim Lahm, Haley Hedlin, Jeffrey R. Fineman, Robert Lafyatis, Carsten N. F. Knutsen, Cristina M. Alvira, David N. Cornfield, Vinicio A. de Jesus Perez |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | European Respiratory Journal. :2201625 |
| ISSN: | 1399-3003 0903-1936 |
| Popis: | IntroductionPulmonary 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.MethodsLung 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).ResultsHealthy 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.ConclusionsWnt7a 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. |
| Databáze: | OpenAIRE |
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