Back to Search
Start Over
PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Mar; Vol. 44 (3), pp. 620-634. Date of Electronic Publication: 2023 Dec 28. - Publication Year :
- 2024
-
Abstract
- Background: The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs.<br />Methods: Using fluid flow system to generate forces on EC and multiscale imaging analyses on ApoE <superscript>-/-</superscript> mice whole arteries, we studied the cellular and molecular mechanism involved in autophagic response to LSS or HSS on the endothelium.<br />Results: We found that LSS and HSS trigger autophagy activation by mobilizing specific autophagic signaling modules. Indeed, LSS-induced autophagy in endothelium was independent of the class III PI3K (phosphoinositide 3-kinase) VPS34 (vacuolar sorting protein 34) but controlled by the α isoform of class II PI3K (phosphoinositide 3-kinase class II α [PI3KCIIα]). Accordingly, reduced PI3KCIIα expression in ApoE <superscript>-/-</superscript> mice (ApoE <superscript>-/-</superscript> PI3KCIIα <superscript>+/-</superscript> ) led to EC dysfunctions associated with increased plaque deposition in the LSS regions. Mechanistically, we revealed that PI3KCIIα inhibits mTORC1 (mammalian target of rapamycin complex 1) activation and that rapamycin treatment in ApoE <superscript>-/-</superscript> PI3KCIIα <superscript>+/-</superscript> mice specifically rescue autophagy in arterial LSS regions. Finally, we demonstrated that absence of PI3KCIIα led to decreased endothelial primary cilium biogenesis in response to LSS and that ablation of primary cilium mimics PI3KCIIα-decreased expression in EC dysfunction, suggesting that this organelle could be the mechanosensor linking PI3KCIIα and EC homeostasis.<br />Conclusions: Our data reveal that mechanical forces variability within the arterial system determines EC autophagic response and supports a central role of PI3KCIIα/mTORC1 axis to prevent EC dysfunction in LSS regions.<br />Competing Interests: Disclosures None.
- Subjects :
- Animals
Humans
Mice
Apolipoproteins E genetics
Apolipoproteins E metabolism
Autophagy
Cells, Cultured
Human Umbilical Vein Endothelial Cells metabolism
Mammals
Mechanistic Target of Rapamycin Complex 1 metabolism
Stress, Mechanical
Atherosclerosis genetics
Atherosclerosis prevention & control
Atherosclerosis metabolism
Class I Phosphatidylinositol 3-Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 44
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 38152888
- Full Text :
- https://doi.org/10.1161/ATVBAHA.123.319978