Jie Ouyang, Haijiao Long, Shuhua Chen, Hong Xiang, Zhihao Shu, Xuewen Wang, Jing Zhang, Huiqin Liu, Baiyi Tang, Jie Xiao, Quanjun Liu, Zishun Zhan, Ruifang Chen, Hongwei Lu
{"title":"S1PR2 Mediates Smooth Muscle Cell Proliferation and Endothelial Cell Permeability via Akt/mTOR and RhoA/ROCK1 in Atherosclerosis","authors":"Jie Ouyang, Haijiao Long, Shuhua Chen, Hong Xiang, Zhihao Shu, Xuewen Wang, Jing Zhang, Huiqin Liu, Baiyi Tang, Jie Xiao, Quanjun Liu, Zishun Zhan, Ruifang Chen, Hongwei Lu","doi":"10.1002/jbt.70351","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Atherosclerosis is a complex disease involving a series of interrelated events, among which endothelial cell dysfunction and vascular smooth muscle cell proliferation play pivotal roles in the early formation of atherosclerotic plaques. Sphingosine 1-phosphate, a product of sphingomyelin metabolism, serves as a signaling molecule implicated in the pathogenesis of atherosclerosis and other conditions by binding to sphingosine 1-phosphate receptors (S1PRs). However, the precise mechanism by which S1PRs influence atherosclerosis remains incompletely understood. Here, we identified a dual role for S1PR2 in vascular cells treated with oxidized-low-density lipoprotein. In smooth muscle cells, decreased S1PR2 upregulated PCNA expression by activating Akt/mTOR, leading to abnormal cell proliferation. Conversely, in endothelial cells, elevated S1PR2 expression reduced VE-cadherin expression by activating the RhoA/ROCK1 pathway, increasing endothelial permeability. In an apolipoprotein E-deficient mouse model, S1PR2 agonist treatment reduced the abnormal proliferation of aortic smooth muscle cells, while S1PR2 antagonist treatment alleviated barrier function damage in aortic endothelial cells. However, both S1PR2 agonist and antagonist treatments showed limited efficacy on aortic plaques due to their opposing effects on endothelial cells and smooth muscle cells. Thus, therapies targeting specific cell types hold significant promise, and S1PR2 may be a potential target for the prevention and treatment of atherosclerosis.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 6","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.70351","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Atherosclerosis is a complex disease involving a series of interrelated events, among which endothelial cell dysfunction and vascular smooth muscle cell proliferation play pivotal roles in the early formation of atherosclerotic plaques. Sphingosine 1-phosphate, a product of sphingomyelin metabolism, serves as a signaling molecule implicated in the pathogenesis of atherosclerosis and other conditions by binding to sphingosine 1-phosphate receptors (S1PRs). However, the precise mechanism by which S1PRs influence atherosclerosis remains incompletely understood. Here, we identified a dual role for S1PR2 in vascular cells treated with oxidized-low-density lipoprotein. In smooth muscle cells, decreased S1PR2 upregulated PCNA expression by activating Akt/mTOR, leading to abnormal cell proliferation. Conversely, in endothelial cells, elevated S1PR2 expression reduced VE-cadherin expression by activating the RhoA/ROCK1 pathway, increasing endothelial permeability. In an apolipoprotein E-deficient mouse model, S1PR2 agonist treatment reduced the abnormal proliferation of aortic smooth muscle cells, while S1PR2 antagonist treatment alleviated barrier function damage in aortic endothelial cells. However, both S1PR2 agonist and antagonist treatments showed limited efficacy on aortic plaques due to their opposing effects on endothelial cells and smooth muscle cells. Thus, therapies targeting specific cell types hold significant promise, and S1PR2 may be a potential target for the prevention and treatment of atherosclerosis.
期刊介绍:
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.