Semaphorin-3E attenuates neointimal formation via suppressing VSMCs migration and proliferation

• Published in: Cardiovascular research Vol. 113; no. 14; pp. 1763 - 1775
• Main Authors: Wu, Jie-Hong, Li, Yanan, Zhou, Yi-Fan, Haslam, James, Elvis, Opoku Nana, Mao, Ling, Xia, Yuan-Peng, Hu, Bo
• Format: Journal Article
• Language: English
• Published: England 01.12.2017
• Subjects: Animals; Carotid Artery Injuries - drug therapy; Carotid Artery Injuries - metabolism; Cell Movement - drug effects; Cell Movement - physiology; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cells, Cultured; Cytoskeletal Proteins; Glycoproteins - metabolism; Humans; Male; Membrane Proteins - metabolism; Mice, Inbred C57BL; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Neointima - drug therapy; Neointima - metabolism; Semaphorins - metabolism; Signal Transduction - drug effects; Migration and proliferation; Neointimal formation; Sema3E; PlexinD1; Vascular smooth muscle cells
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvx190

The migration and proliferation of vascular smooth muscle cells (VSMCs) are crucial events in the neointimal formation, a hallmark of atherosclerosis and restenosis. Semaphorin3E (Sema3E) has been found to be a critical regulator of cell migration and proliferation in many scenarios. However, its role on VSMCs migration and proliferation is unclear. This study aimed to investigate the effect of Sema3E on VSMCs migration, proliferation and neointimal formation, and explore possible mechanisms. We found that the expression of Sema3E was progressively decreased during neointimal formation in a carotid ligation model. H&E-staining showed lentivirus-mediated overexpression of Sema3E in carotid ligation area attenuated neointimal formation. Immunofluorescence staining showed that the receptor (PlexinD1) of Sema3E was expressed in vascular walls. In cultured mouse VSMCs, Sema3E inhibited VSMCs migration and proliferation via plexinD1 receptor. The inhibitory effect was mediated, at least in part, by inactivating Rap1-AKT signalling pathways in VSMCs. Moreover, we found that PDGFBB down-regulated the expression of Sema3E in VSMCs and Sema3E notably inhibited the expression of PDGFB in endothelial cells. In addition, the number of Sema3E-positive VSMCs was diminished in plaques of atherosclerotic patients. Results from a public GEO microarray database showed a negative correlation between Sema3E and PDGFB transcriptional levels in the human plaques examined. Our study demonstrates that Sema3E/plexinD1 inhibits proliferation and migration of VSMCs via inactivation of Rap1-AKT signalling pathways. The mutual inhibition between PDGF-BB and Sema3E after vascular injury plays a critical role in the process of neointimal formation.