Integrin affinity modulation critically regulates atherogenic endothelial activation in vitro and in vivo

• Type of Material: Article
• Authors: Zaki Al-Yafeai, Emory University; Brenna H Pearson, Emory University; Jonette M Peretik, Emory University; Elizabeth D Cockerham, Emory University; Kaylea A Reeves, Emory University; Umesh Bhattarai, Emory University; Dongdong Wang, Emory University; Brian Petrich, Emory University; Wayne A Orr, Emory University
• Language: English
• Date: 2021-02-18
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.matbio.2020.10.006
• Title of Journal or Parent Work: MATRIX BIOLOGY
• Volume: 96
• Start Page: 87
• End Page: 103
• Grant/Funding Information: This work was supported by National Heart, Lung, and Blood Institute R01 HL098435, HL133497, HL141155, and GM121307 (to A.W.O.), R01 HL117061 (to B.G.P.), by an American Heart Association Pre-doctoral Fellowship (19PRE34380751) and Malcolm Feist Cardiovascular Research Endowment Pre-doctoral Fellowship (to Z.A.Y.).
• Keywords: Science & Technology; CELLS; Inflammation; Integrin; NF-KAPPA-B; Oxidized LDL; ADHESION; DYSFUNCTION; TALIN; Talin1; FLOW; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; EXPRESSION; ALPHA-V-BETA-3; Shear Stress; Cell Biology; FIBRONECTIN DEPOSITION; ALPHA-5-BETA-1

Abstract

While vital to platelet and leukocyte adhesion, the role of integrin affinity modulation in adherent cells remains controversial. In endothelial cells, atheroprone hemodynamics and oxidized lipoproteins drive an increase in the high affinity conformation of α5β1 integrins in endothelial cells in vitro, and α5β1 integrin inhibitors reduce proinflammatory endothelial activation to these stimuli in vitro and in vivo. However, the importance of α5β1 integrin affinity modulation to endothelial phenotype remains unknown. We now show that endothelial cells (talin1 L325R) unable to induce high affinity integrins initially adhere and spread but show significant defects in nascent adhesion formation. In contrast, overall focal adhesion number, area, and composition in stably adherent cells are similar between talin1 wildtype and talin1 L325R endothelial cells. However, talin1 L325R endothelial cells fail to induce high affinity α5β1 integrins, fibronectin deposition, and proinflammatory responses to atheroprone hemodynamics and oxidized lipoproteins. Inducing the high affinity conformation of α5β1 integrins in talin1 L325R endothelial cells suggest that NF-κB activation and maximal fibronectin deposition require both integrin activation and other integrin-independent signaling. In endothelial-specific talin1 L325R mice, atheroprone hemodynamics fail to promote inflammation and macrophage recruitment, demonstrating a vital role for integrin activation in regulating endothelial phenotype.