Shear-Regulated Extracellular Microenvironments and Endothelial Cell Surface Integrin Receptors Intertwine in Atherosclerosis.

Fan-E Mo

doi:10.3389/fcell.2021.640781

Abstract

Mechanical forces imposed by blood flow shear stress directly modulate endothelial gene expression and functional phenotype. The production of extracellular matrix proteins and corresponding cell-surface integrin receptors in arterial endothelial cells is intricately regulated by blood flow patterns. Laminar blood flow promotes mature and atheroresistant endothelial phenotype, while disturbed flow induces dysfunctional and atheroprone endothelial responses. Here, we discuss how hemodynamic changes orchestrate the remodeling of extracellular microenvironments and the expression profile of the integrin receptors in endothelial cells leading to oxidative stress and inflammation. Targeting the interaction between matrix proteins and their corresponding integrins is a potential therapeutic approach for atherosclerosis.

Highlights

Though risk factors, such as hyperlipidemia, hypertension, and hyperglycemia, pose a threat to the entire arterial system, atherosclerosis preferentially occurs at arterial branches or curvatures, where the local blood flow is disturbed (Chiu and Chien, 2011)
Endothelial dysfunction by disturbed flow is manifested by the lack of nitric oxide production, and chronic inflammatory response mediated through the pleiotropic transcription factor nuclear factor-κB (NF-κB; Gimbrone and Garcia-Cardena, 2016)
No available treatments directly target the dysfunctional endothelium in atherosclerosis

Summary

INTRODUCTION

Though risk factors, such as hyperlipidemia, hypertension, and hyperglycemia, pose a threat to the entire arterial system, atherosclerosis preferentially occurs at arterial branches or curvatures, where the local blood flow is disturbed (Chiu and Chien, 2011). Endothelial dysfunction by disturbed flow is manifested by the lack of nitric oxide production, and chronic inflammatory response mediated through the pleiotropic transcription factor nuclear factor-κB (NF-κB; Gimbrone and Garcia-Cardena, 2016) These atheroprone genes include cell-surface adhesion molecules (such as vascular cell adhesion molecule-1; Korenaga et al, 1997), secreted cytokines (such as interleukin-1 and monocyte chemoattractant protein 1; Hsu et al, 2019), and prothrombotic mediators (such as von Willebrand factor; Zhu et al, 2020). The critical role in atherogenesis and the accessibility of matrix/ integrin engagement makes it an attractive therapeutic target for atherosclerosis This minireview summarizes recent findings on the shear-induced ECM remodeling and integrin expression, and their roles in atherosclerosis (Figure 1)

BASEMENT MEMBRANE

MATRICELLULAR PROTEINS

DISCUSSION