Abstract 12164: Nectin-like Molecule-5 Regulates Formation of Intimal Thickening in Mouse Carotid Artery and Phenotypic Reversion of Vascular Smooth Muscle Cells
Background: Intimal thickening is a phenomenon that is observed at the very early stage of atherosclerosis. It is considered that this phenomenon involves the phenotypic reversion of medial smooth muscle cells (SMCs) from a differentiated to a dedifferentiated state and their subsequent migration into intima and proliferation. We recently reported that the immunoglobulin-like molecule nectin-like molecule (Necl)-5 enhances migration and proliferation of endothelial cells and angiogenesis. Therefore, we anticipated that Necl-5 is involved in intimal thickening. We examined here the roles of Necl-5 in intimal thickening following carotid artery ligation in mice and in phenotypic reversion, migration, and proliferation of cultured SMCs.
Methods and Results: In vivo, Necl-5 was upregulated in SMCs of the thickened neointima in wild-type (WT) mice at 4 weeks after carotid artery ligation. Compared with that in WT mice, the intimal thickening was less severe in Necl-5 knockout (KO) mice (Intima/media ratio; WT vs. Necl-5 KO = 1.17±0.22 vs. 0.41±0.14, p=0.013). BrdU incorporation in the thickened intima of ligated carotid arteries was decreased in Necl-5 KO mice compared with WT mice at 2 weeks after carotid artery ligation. In vitro, compared with mouse aortic SMCs (MASMCs) isolated from WT mice, the expression levels of differentiation marker genes, such as SM α-actin, SM22α, and SM-myosin heavy chain, were higher, whereas that of SMemb, a dedifferentiation marker gene, was lower in MASMCs isolated from Necl-5 KO mice. Migration, proliferation, and extracellular signal-regulated kinase (ERK) activity in response to serum were reduced in Necl-5 KO MASMCs compared with WT MASMCs. In WT MASMCs, inhibition of ERK activity increased the expression levels of differentiation marker genes and decreased migration and proliferation in response to serum.
Conclusions: These findings indicate that Necl-5 regulates ERK activation, which enhances the phenotypic reversion, migration, and proliferation of SMCs, and promotes the formation of intimal thickening following carotid artery ligation. This study reveals Necl-5 as a candidate target molecule for the prevention of atherosclerosis.
- © 2012 by American Heart Association, Inc.