Background—Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y₁₂ receptor (P2Y₁₂) plays a central role in amplifying platelet aggregation, dense granule and -granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y₁₂ deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models.

Methods and Results—P2Y₁₂-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 P2Y₁₂ in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y₁₂^-/- 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 P2Y₁₂^+/+ compared with P2Y₁₂^-/- animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y₁₂ versus platelet P2Y₁₂. 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 P2Y₁₂ in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.