β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration

Abstract

Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins β-arrestin1 and -2 might regulate this pathological process. Deficiency of β-arrestin2 in ldlr−/− mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that β-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, β-arrestin1−/−, and β-arrestin2−/− mice. Neointimal hyperplasia was enhanced in β-arrestin1−/− mice, and diminished in β-arrestin2−/− mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in β-arrestin2−/− mice was not altered by transplantation with either wild-type or β-arrestin2−/− bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in β-arrestin1−/− and decreased in β-arrestin2−/− mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in β-arrestin1−/− SMCs and less in β-arrestin2−/− SMCs. Proliferation was less than wild type in β-arrestin2−/− SMCs but not in β-arrestin2−/− endothelial cells. We conclude that β-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by β-arrestin2 and β-arrestin1. These findings identify inhibition of β-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.