title: Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61.
abstract: Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA1-/-, LPA2-/-, and LPA3-/-) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA1deficiency, but not LPA2or LPA3deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA1-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Feng
authors.initials: F
authors.lastname: Hao
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.|Science Research Center, China-Japan Union Hospital of Jilin University, Changchun, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Daniel Dongwei
authors.initials: DD
authors.lastname: Wu
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Dong
authors.initials: D
authors.lastname: An
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.|College of Environmental and Resource Sciences, Shanxi University, Taiyuan, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, Louisiana State University Health Science Center in Shreveport, Shreveport, Louisiana.
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee; cuim@utk.edu.
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D008077:Lipoproteins, LDL / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000139:chemically induced* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D016326:Extracellular Matrix Proteins; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C099252:oxidized low density lipoprotein; C032881:lysophosphatidic acid
keywords: CCN1; lysophosphatidic acid; smooth muscle cells; vascular neointimal formation