Shear‐responsive miR‐155 Regulates Endothelial Cell Phenotype and Function

Abstract

In endothelial cells (ECs), unidirectional shear stress (USS) changes gene expression and promotes an atheroprotective cell phenotype, whereas low or oscillatory shear stress induces an atherogenic phenotype. We found that miR‐155 expression was increased 4 fold in response to USS, compared to oscillatory shear stress conditions. Transfection of miR‐155 mimic into human ECs dramatically altered the actin cytoskeleton organization. ECs overexpressing miR‐155 had less F‐ actin and less focal adhesions, indicated by a decrease in Vinculin and p‐FAK protein (p=0.016 and p=0.018). Furthermore, miR‐155 suppressed two key regulators of the EC cytoskeleton: RhoA (decreased 75%) and myosin light chain kinase (MYLK, decreased 40%). These miR‐ 155 mediated changes were associated with less EC migration (p=0.0106) and proliferation (p=0.0002). Also, ECs overexpressing miR‐155 showed less monocyte adhesion compared to control cells (p=0.0002). In vivo, miR‐155 expression was increased in the atheroprotected thoracic aorta (p=0.0012), where shear stress is unidirectional, compared to the atherosusceptible lower curvature of the aortic arch, where shear stress is low. In conclusion, we demonstrate that miR‐155 expression is regulated by shear‐stress in vitro and in vivo and suggest that miR‐155 induced changes in RhoA and MYLK expression are important for maintaining an atheroprotective phenotype in human ECs.