Cholesterol binding to VCAM-1 promotes vascular inflammation

• Published in: bioRxiv
• Main Authors: Kennelly, John P, Xiao, Xu, Gao, Yajing, Kim, Sumin, Hong, Soon-Gook, Villanueva, Miranda, Ferrari, Alessandra, Vanharanta, Lauri, Nguyen, Alexander, Nagari, Rohith T, Burton, Nikolas R, Tol, Marcus J, Becker, Andrew P, Lee, Min Jae, Ikonen, Elina, Backus, Keriann M, Mack, Julia J, Tontonoz, Peter
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory 18.09.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.09.17.613543

Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endothelium dampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.