RGMa promotes dedifferentiation of vascular smooth muscle cells into a macrophage-like phenotype in vivo and in vitro

Abstract

Repulsive guidance molecule a (RGMa) is a glycosylphosphatidylinositol-anchored glycoprotein that has been demonstrated to influence inflammatory-related diseases in addition to regulating neuronal differentiation and survival during brain development. However, any function or mechanism of RGMa in dedifferentiation of contractile vascular smooth muscle cells (VSMCs) during inflammatory-related atherosclerosis is poorly understood. In the current study, we found that RGMa is expressed in VSMCs-derived macrophage-like cells from the fibrous cap of type V atherosclerotic plaques and the neointima of ligated carotid artery in ApoE^-/- mice. We determined levels of RGMa mRNA and protein increased in oxidized LDL (ox-LDL)-induced VSMCs. Knockdown of RGMa, both in vivo and in vitro, inhibited the dedifferentiation of ox-LDL-induced VSMCs and their ability to proliferate and migrate, reduced the thickness of the neointima after ligation of the left common carotid artery in ApoE^-/- mice. Additionally, we show RGMa promoted the dedifferentiation of VSMCs via enhancement of the role of transcription factor Slug. Slug knockdown reversed the dedifferentiation of ox-LDL-induced VSMCs promoted by RGMa overexpression. Thus, inhibition of RGMa may constitute a therapeutic strategy for atherosclerotic plaques prone to rupture and restenosis following mechanical injury.

Keywords: RGMa; Slug; VSMCs; atherosclerosis; carotid artery ligation; dedifferentiation; neointima; oxidized LDL.