Importance of Platelet Phospholipase Cγ2 Signaling in Arterial Thrombosis as a Function of Lesion Severity

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Abstract
Objective— Platelet activation occurs in response to adhesion receptors for von Willebrand factor (GPIb-V-IX) and collagen (GPVI and α 2 β 1 integrin) acting upstream of phospholipase C (PLC) γ2. However, PLCβ transduces signals from Gαq 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, PLCγ2 knockout mice were studied in blood perfusion assays over fibrillar collagen and in a laser-induced mesenteric artery model of thrombosis. In vitro, PLCγ2-deficient platelets formed a single layer incapable of generating a thrombus on collagen, whereas Gαq-deficient platelets formed reduced size aggregates compared with wild-type cells. In the in vivo model, PLCγ2 −/− 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 Gαq −/− mice in both levels of injury. Conclusions— These results demonstrate that signaling through PLCγ2 plays an important role in arterial thrombosis, but that its contribution depends on the severity of the vascular lesion.