The fundamental role of platelets in atherothrombosis is well defined but the extent of their role in early atherogenesis remains unclear. The P2Y12 receptor is responsible for amplifying and sustaining the platelet activation response and P2Y12 inhibition has been shown to be crucial in modulating the vessel wall response to injury. We therefore hypothesise that P2Y12 activation is important in atherogenesis.
ApoE−/− and ApoE−/−P2Y12−/− mice were fed either a chow or western diet for 12 weeks and atherosclerotic burden was assessed by en face Oil Red O staining of whole aortae and histological analysis of the aortic sinus and brachiocephalic artery. Bone marrow transplants were performed to determine the roles of platelet versus vessel wall P2Y12 in early atherogenesis following 4 weeks of western diet.
Oil Red O staining showed no difference in total lesion area between ApoE−/−P2Y12−/− and ApoE−/− mice for either diet when assessing the aorta as a whole. However, further analysis of the aortic arch alone uncovered a significant reduction in atheroma in ApoE−/−P2Y12−/− mice fed a western diet (8.54±0.85 versus 16.67±1.25 %; P<0.0001). Similarly histological analysis revealed attenuated lesion area in the brachiocephalic artery (P<0.05) but not in the aortic sinus. Bone marrow transplants demonstrated that mice deficient in vessel wall P2Y12, regardless of platelet P2Y12 expression, had significantly reduced atheroma in both the aortic sinus and brachiocephalic artery (P<0.001).
This work identifies an important role for vessel wall P2Y12 in promoting early atherogenesis. Despite the proven role of platelets in atherothrombosis and the profound effect of P2Y12 on platelet reactivity, we found no platelet P2Y12 effect on early atherogenesis. Published data has linked P2Y12 expression with vascular smooth muscle cell mitogenesis, providing a potential mechanism for the effects seen in these results.