A PI3KCIIALPHA/primary cilium-dependent autophagy program protects endothelial cells in response to atheroprone shear stress

Abstract

Background and Aims : The ability to generate and respond to mechanical forces is a basic requirement for maintaining cell homeostasis. This is of particular importance for the cardiovascular system which is subjected to different mechanical forces such as Low and High shear stresses (LSS and HSS). Autophagy is involved in endothelial cells (ECs) response to HSS generated by blood flow. However, it is still unclear whether the variability of shear stress triggers specific autophagic response in ECs. Methods: We used fluid flow chamber system to generate different mechanical forces on ECs in vitro and we specifically studied LSS and HSS artery territories, referred as aortic arch and descending aorta respectively, in mice susceptible to atherosclerosis. Results: We found that LSS and HSS mobilize two different signalling modules relying on class II PI3K (PI3KCIIα) and III PI3K/Vps34 respectively to induce autophagy. We demonstrated that LSS-induced autophagy required the primary cilium and is critical to prevent ECs permeability and integrity. Accordingly, atherogenic stress or reduced PI3KCIIα expression led to a decrease in the ciliated ECs associated with decreased autophagic flux and accelerated plaque deposition in the LSS regions. Furthermore, we revealed that PI3KCIIα controls mTORC1 activation. Notably, mTORC1 inhibition impaired atherosclerosis development in ApoE-/- PI3KCIIα+/- mice and led to primary cilium restoration suggesting a crosstalk between primary cilium biogenesis and autophagy in LSS context. Conclusions: Our data reveal that mechanical forces variability within arterial system determine ECs autophagic response and support a central role of PI3KCIIα/mTOR axis in EC mechanosensing in atheroprone regions.