title: Direct Evidence for P2Y2 Receptor Involvement in Vascular Response to Injury.
abstract: OBJECTIVE
  Extracellular nucleotide release at the site of arterial injury mediates the proliferation and migration of vascular smooth muscle cells. Our aim was to investigate the role of the P2Y2 nucleotide receptor (P2Y2R) in neointimal hyperplasia. Approach and Results: Vascular injury was induced by the implantation of a polyethylene cuff around the femoral artery in wild-type and P2Y2R-deficient mice (P2Y2R-/-). Electron microscopy was used to analyze monocyte and lymphocyte influx to the intima 36 h after injury. Compared to wild-type littermates, P2Y2R-/- mice exhibited a 3-fold decreased number of mononuclear leukocytes invading the intima (p < 0.05). Concomitantly, the migration of smooth muscle cells was decreased by more than 60% (p < 0.05), resulting in a sharp inhibition of intimal thickening formation in P2Y2R-/- mice (n = 15) 14 days after cuff placement. In vitro, loss of P2Y2R significantly impaired monocyte migration in response to nucleotide agonists. Furthermore, transgenic rats overexpressing the P2Y2R developed accelerated intimal lesions resulting in more than 95% luminal stenosis (p < 0.05, n = 10).
  
  
  CONCLUSIONS
  Loss- and gain-of-function approaches established direct evidence for P2Y2R involvement in neointimal hyperplasia. Specific anti-P2Y2R therapies may be used against restenosis and bypass graft failure.
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, Mont., USA.
authors.forename: Yuksel
authors.initials: Y
authors.lastname: Agca
authors.forename: Shaomin
authors.initials: S
authors.lastname: Qian
authors.forename: Cansu
authors.initials: C
authors.lastname: Agca
authors.forename: Cheikh I
authors.initials: CI
authors.lastname: Seye
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease; D006965:Hyperplasia; D008214:Lymphocytes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D058426:Neointima; D010641:Phenotype; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D058473:Receptors, Purinergic P2Y2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D058912:Purinergic P2Y Receptor Agonists; D058473:Receptors, Purinergic P2Y2