Platelet P2Y 12 Receptor Influences the Vessel Wall Response to Arterial Injury and Thrombosis

Abstract

Background— Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y 12 receptor (P2Y 12 ) plays a central role in amplifying platelet aggregation, dense granule and α-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y 12 deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. Methods and Results— P2Y 12 -deficient (−/−) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y 12 in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y 12 −/− arteries was significantly less than that observed in control strain arteries ( P <0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y 12 +/+ compared with P2Y 12 −/− animals ( P <0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y 12 versus platelet P2Y 12 . Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in −/− to +/+ animals than in the positive (+/+ to +/+) control group ( P <0.01). Conclusions— These data demonstrate a role for platelet P2Y 12 in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.