Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61

  • Am J Physiol Cell Physiol. 2016 Dec 1;311(6):C975-C984. doi: 10.1152/ajpcell.00227.2016.
Feng Hao  1 ,  Fuqiang Zhang  1  2 ,  Daniel Dongwei Wu  1 ,  Dong An  1 ,  Jing Shi  1  3 ,  Guohong Li  4 ,  Xuemin Xu  1 ,  Mei-Zhen Cui  5
Affiliations
  • 1. Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee.
  • 2. Science Research Center, China-Japan Union Hospital of Jilin University, Changchun, China.
  • 3. College of Environmental and Resource Sciences, Shanxi University, Taiyuan, China; and.
  • 4. Department of Neurosurgery, Louisiana State University Health Science Center in Shreveport, Shreveport, Louisiana.
  • 5. Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee; [email protected].
PMID: 27760754 DOI: 10.1152/ajpcell.00227.2016
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 LPA1 deficiency, but not LPA2 or LPA3 deficiency, prevents LPA-induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1 deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1 is 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.

Keywords
CCN1; lysophosphatidic acid; smooth muscle cells; vascular neointimal formation.
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