ENDOTHELIAL AUTOPHAGY AS A KEY MECHANISM IN ARTERIAL DISEASES

Abstract

Blood flow imposes shear stress on endothelial cells (ECs). ECs are able to convert these mechanical stimuli into intracellular signals that affect cellular function. As deregulated autophagy is associated with an acceleration of a variety of cardiovascular and metabolic diseases where impaired flow-mediated EC responses promote cardiovascular risk, we hypothesized that endothelial autophagy and endothelial function interact. We found that defective endothelial autophagy, caused by targeted deletion of the Atg5 gene in ECs alone, results in selective loss of flow-induced vasodilation in mesenteric arteries and in kidneys ex vivo; this leads to increased cerebral and renal vascular resistance in vivo. Furthermore, we find a crucial pathophysiological role for endothelial autophagy in flow-mediated outward arterial remodelling, prevention of neointima formation following wire injury and recovery after myocardial infarction. Together, these findings unravel a fundamental role for autophagy in endothelial function, linking cell proteostasis to mechanosensing signaling that will be discussed. These findings also open new questions regarding the potential role of endothelial proteostasis in arterial diseases.