Autophagy protein 5 controls flow-dependent endothelial functions
Pierre Nivoit, Thomas Mathivet, Junxi Wu, Yann Salemkour, Devanarayanan Siva Sankar, Véronique Baudrie, Jennifer Bourreau, Anne‐Laure Guihot, Emilie Vessières, Mathilde Lemitre, Cinzia Bocca, Jérémie Teillon, Morgane Le Gall, Anna Chipont, Estelle Robidel, Neeraj Dhaun, Eric Camerer, Pascal Reynier, Étienne Roux, Thierry Couffinhal, Patrick W. F. Hadoke, Jean‐Sébastien Silvestre, Xavier Guillonneau, Philippe Bonnin, Daniel Henrion, Jörn Dengjel, Pierre‐Louis Tharaux, Olivia Lenoir
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.