Importance of platelet phospholipase Cγ2 signaling in arterial thrombosis as a function of lesion severity

Objective - Platelet activation occurs in response to adhesion receptors for von Willebrand factor (GPIb-V-IX) and collagen ( GPVI and alpha(2)beta(1) integrin) acting upstream of phospholipase C ( PLC) gamma 2. However, PLC beta transduces signals from G alpha q protein-coupled receptors for soluble agonists (P2y(1), TxA(2)/TP, and thrombin/PAR). A Gi-dependent pathway amplifies most of these responses. Methods and Results - To evaluate the role of adhesion receptors signaling in arterial thrombosis, PLC gamma 2 knockout mice were studied in blood perfusion assays over fibrillar collagen and in a laser-induced mesenteric artery model of thrombosis. In vitro, PLC gamma 2-deficient platelets formed a single layer incapable of generating a thrombus on collagen, whereas G alpha q-deficient platelets formed reduced size aggregates compared with wild-type cells. In the in vivo model, PLC gamma 2(-/-) mice displayed defective thrombus formation in superficial lesions but productive thrombosis after a more severe laser injury. In contrast, resistance to thrombosis was observed in G alpha q(-/-) mice in both levels of injury. Conclusions - These results demonstrate that signaling through PLC gamma 2 plays an important role in arterial thrombosis, but that its contribution depends on the severity of the vascular lesion.