title: Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells.
abstract: Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin α5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin α5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin α5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin α5 translocation and activation. In vivo, integrin α5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, and knockdown of integrin α5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin α5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin- and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China; Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China;
authors.forename: Mingxia
authors.initials: M
authors.lastname: Gu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China;
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China;
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; shuchien@ucsd.edu john.shyy@mail.xjtu.edu.cn zhuyi@tmu.edu.cn.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China; shuchien@ucsd.edu john.shyy@mail.xjtu.edu.cn zhuyi@tmu.edu.cn.
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China shuchien@ucsd.edu john.shyy@mail.xjtu.edu.cn zhuyi@tmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D039482:Integrin alpha5 / Q000378:metabolism*; D008297:Male; D008560:Membrane Fluidity; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport; D011973:Receptors, LDL / Q000378:metabolism; D012212:Rheology; D033081:Shear Strength; D013314:Stress, Mechanical
chemical_list: D000199:Actins; D039482:Integrin alpha5; D011973:Receptors, LDL; D002784:Cholesterol
keywords: endothelial dysfunction; integrin; lipid rafts; proteomics; shear stress