Vessel wall, not platelet, P2Y12 potentiates early atherogenesis

Platelets have a fundamental role in atherothrombosis, but their role in early atherogenesis is unclear. The P2Y(12) receptor is responsible for amplifying and sustaining platelet activation and P2Y(12) inhibition is crucial in modulating the vessel wall response to injury. We therefore examined the role of platelet vs. vessel wall P2Y(12) in early atherogenesis and considered the use of P2Y(12) antagonists ticagrelor and clopidogrel in modulating this process. ApoE(-/-) and ApoE(-/-)P2Y(12)(-/-) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden. Compared with ApoE(-/-) controls, platelet P2Y(12) deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation, whereas vessel wall P2Y(12) deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery (both P < 0.001). ApoE(-/-) and ApoE(-/-)P2Y(12)(-/-) male mice fed western diet plus either twice-daily doses of ticagrelor (100 mg/kg) or daily clopidogrel (20 mg/kg) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol. Attenuated P-selectin expression confirmed platelet P2Y(12) inhibition in drug-treated mice. Despite its major contribution to platelet reactivity, platelet P2Y(12) has no effect on early atheroma formation, whereas vessel wall P2Y(12) is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y(12) inhibitors may not be effective in preventing early disease.