Direct Evidence for P2Y2 Receptor Involvement in Vascular Response to Injury

Objectives: 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 P2Y 2 nucleotide receptor (P2Y 2 R) 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 P2Y 2 R-deficient mice (P2Y 2 R -/- ). Electron microscopy was used to analyze monocyte and lymphocyte influx to the intima 36 h after injury. Compared to wild-type littermates, P2Y 2 R -/- 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 P2Y 2 R -/- mice (n = 15) 14 days after cuff placement. In vitro, loss of P2Y 2 R significantly impaired monocyte migration in response to nucleotide agonists. Furthermore, transgenic rats overexpressing the P2Y 2 R 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 P2Y 2 R involvement in neointimal hyperplasia. Specific anti-P2Y 2 R therapies may be used against restenosis and bypass graft failure.