Nectin-Like Molecule-5 Regulates Intimal Thickening After Carotid Artery Ligation in Mice
Objective—Intimal thickening is considered to result from the dedifferentiation of medial smooth muscle cells (SMCs) from a contractile to a synthetic phenotype, and their subsequent migration and proliferation. It is unknown whether nectin-like molecule (Necl)-5, which is overexpressed in cancer cells, is involved in intimal thickening.
Approach and Results—Necl-5 was upregulated in mouse carotid artery after ligation. Compared with wild-type mice, intimal thickening after carotid artery ligation was milder in Necl-5 knockout mice. In vitro, the expression levels of SMC differentiation markers were higher, whereas the expression level of an SMC dedifferentiation marker was lower, in Necl-5 knockout mouse aortic SMCs (MASMCs) compared with wild-type MASMCs. The migration, proliferation, and extracellular signal–regulated kinase activity in response to serum were decreased in Necl-5 knockout MASMCs compared with wild-type MASMCs. In wild-type MASMCs, inhibition of extracellular signal–regulated kinase activity increased the expression levels of SMC differentiation markers and decreased their migration and proliferation in response to serum.
Conclusions—The present findings indicate that Necl-5 plays a role in the formation of intimal thickening after carotid artery ligation by regulating dedifferentiation, migration, and proliferation of SMCs in an extracellular signal–regulated kinase-dependent manner. Our results suggest that Necl-5 may represent a potential therapeutic target to limit intimal thickening after vascular injury.
- Received June 14, 2012.
- Accepted March 11, 2013.
- © 2013 American Heart Association, Inc.