Autophagy protein 5 controls flow-dependent endothelial functions

Nivoit, Pierre and Mathivet, Thomas and Wu, Junxi and Salemkour, Yann and Sankar, Devanarayanan Siva and Baudrie, Véronique and Bourreau, Jennifer and Guihot, Anne-Laure and Vessieres, Emilie and Lemitre, Mathilde and Bocca, Cinzia and Teillon, Jérémie and Le Gall, Morgane and Chipont, Anna and Robidel, Estelle and Dhaun, Neeraj and Camerer, Eric and Reynier, Pascal and Roux, Etienne and Couffinhal, Thierry and Hadoke, Patrick W. F. and Silvestre, Jean-Sébastien and Guillonneau, Xavier and Bonnin, Philippe and Henrion, Daniel and Dengjel, Joern and Tharaux, Pierre-Louis and Lenoir, Olivia (2023) Autophagy protein 5 controls flow-dependent endothelial functions. Experientia, 80 (8). 210. ISSN 1420-9071 (https://doi.org/10.1007/s00018-023-04859-9)

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Abstract

Dysregulated autophagy is associated with cardiovascular and metabolic diseases, where impaired flow-mediated endothelial cell responses promote cardiovascular risk. The mechanism by which the autophagy machinery regulates endothelial functions is complex. We applied multi-omics approaches and in vitro and in vivo functional assays to decipher the diverse roles of autophagy in endothelial cells. We demonstrate that autophagy regulates VEGF-dependent VEGFR signaling and VEGFR-mediated and flow-mediated eNOS activation. Endothelial ATG5 deficiency in vivo results in selective loss of flow-induced vasodilation in mesenteric arteries and kidneys and increased cerebral and renal vascular resistance in vivo. We found a crucial pathophysiological role for autophagy in endothelial cells in flow-mediated outward arterial remodeling, prevention of neointima formation following wire injury, and recovery after myocardial infarction. Together, these findings unravel a fundamental role of autophagy in endothelial function, linking cell proteostasis to mechanosensing.

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