Sphigosine-1-phosphate receptor 1 promotes neointimal hyperplasia in a mouse model of carotid artery injury

• Published in: Biochemical and biophysical research communications 2019-03, Vol.511 (1), p.179-184
• Main Authors: Kitano, Teppei, Usui, Soichiro, Takashima, Shin-ichiro, Inoue, Oto, Goten, Chiaki, Nomura, Ayano, Yoshioka, Kazuaki, Okajima, Masaki, Kaneko, Shuichi, Takuwa, Yoh, Takamura, Masayuki
• Format: Article
• Language: English
• Subjects: Animals; Carotid Arteries - metabolism; Carotid Arteries - pathology; Carotid Artery Injuries - genetics; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Cell Proliferation; Disease Models, Animal; Hyperplasia - genetics; Hyperplasia - metabolism; Hyperplasia - pathology; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Neointima - genetics; Neointima - metabolism; Neointima - pathology; Neointima hyperplasia; Sphingosine-1-phosphate; Sphingosine-1-Phosphate Receptors - analysis; Sphingosine-1-Phosphate Receptors - genetics; Sphingosine-1-Phosphate Receptors - metabolism; Up-Regulation; Vascular smooth muscle cell
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.02.047

Vascular remodeling, resulting from proliferation and migration of vascular smooth muscle cells (VSMCs), is a major cause of atherosclerosis and restenosis. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates proliferation and migration of VSMCs via S1P-specific G protein-coupled receptors, including S1P receptor 1 (S1PR1) to S1PR3. However, the role of S1PR1 in vascular remodeling is not well understood. Therefore, in this study, we aimed to investigate the effect of S1PR1 on neointimal hyperplasia in a carotid artery ligation mouse model using transgenic C57Bl/6 mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. We found that S1PR1 expression in carotid artery was upregulated after carotid artery ligation in non-transgenic (nTg) mice. Tg-S1PR1 mice showed enhanced ligation-induced neointimal hyperplasia with increased neointimal cell proliferation, compared with control nTg mice. VSMCs isolated from Tg-S1PR1 mice showed enhanced proliferation and migration in response to S1P stimulation. VSMCs from Tg-S1PR1 mice showed greater expression of interleukin-6 (IL-6) compared with nTg mouse-derived VSMCs, and administration of IL-6-neutralizing antibody into Tg-S1PR1 mice suppressed neointimal hyperplasia. These results suggest that S1P-S1PR1 signaling plays an important role in neointimal hyperplasia after vascular injury via IL-6 production. •Sphingosine-1-phosphate receptor 1 (S1PR1) expression in carotid artery was upregulated after carotid artery ligation.•Overexpression of S1PR1 (Tg-S1PR1) in vascular smooth muscle cells (VSMC) enhances ligation-induced neointimal hyperplasia.•VSMCs obtained from Tg-S1PR1 increases expression of interleukin-6 (IL-6).•Administration of IL-6 neutralizing antibody suppresses neointimal hyperplasia after ligation.