Abstract 13231: Semaphorin3F Reduces Atherosclerosis by Decreasing Endothelial Activation and Barrier Permeability and Smooth Muscle Cell Migration

Abstract

Coronary artery disease (CAD) remains a leading cause of death worldwide. To identify genes causally linked to CAD, we previously conducted large-scale genetic analyses, and identified an association between genes in the semaphorin pathway and CAD. Expression profiling in human atherosclerosis-relevant cell types and atherosclerotic plaques identified semaphorin3F (SEMA3F) as a possible candidate causally linked to atherosclerosis. Administration of SEMA3F reduced aortic lesion area in western-type diet-fed Ldlr -/- mice (Control: 12.1±1.4; SEMA3F: 8.1±0.8, % lesion area/total aortic sinus area, p=0.02). In contrast, neointimal formation was increased in Sema3f -/- mice with partial carotid artery ligation ( WT : 22.8±2.8; Sema3f -/- : 39.2±4.0; % intimal area/total vessel area, p=0.004). Additionally, SEMA3F administration increased re-endothelialization and reduced restenosis in Ldlr -/- mice that underwent carotid endothelial denudation (Control: 53.3±3.5; SEMA3F: 21.4±3.1; % intimal plaque area/vessel area, p=0.0006). Monocyte adhesion to aortic vascular endothelial cells (VECs) from Sema3f -/- mice was elevated, driven by increased NF-κB activation and increased expression of its target adhesion molecules, VCAM1 and ICAM1, in VECs. Monocyte transmigration through VECs from Sema3f -/- mice was also increased, likely due to increased membrane permeability, assessed by in-vivo intravital two-photon microscopy. The increased membrane permeability was modulated in part by decreased mTOR phosphorylation that in turn suppressed vascular endothelial cadherin protein expression. SEMA3F increased thick actomyosin filaments and elicited larger focal adhesions in VECs, suggesting decreased migration. In line with this, SEMA3F inhibited vascular smooth muscle cell (VSMC) migration and maintained the contractile phenotype of VSMCs, which was mediated by the Rho pathway. SEMA3F is causally atheroprotective in models of atherosclerosis and restenosis, mediated, in part, through the modulation of vascular endothelial cell permeability and adhesion molecule expression, and vascular smooth muscle cell migration and phenotype switching.