Importance of platelet phospholipase Cgamma2 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 alpha2beta1 integrin) acting upstream of phospholipase C (PLC) gamma2. However, PLCbeta transduces signals from Galphaq protein-coupled receptors for soluble agonists (P2y1, TxA2/TP, and thrombin/PAR). A Gi-dependent pathway amplifies most of these responses.


RESULTS
To evaluate the role of adhesion receptors signaling in arterial thrombosis, PLCgamma2 knockout mice were studied in blood perfusion assays over fibrillar collagen and in a laser-induced mesenteric artery model of thrombosis. In vitro, PLCgamma2-deficient platelets formed a single layer incapable of generating a thrombus on collagen, whereas Galphaq-deficient platelets formed reduced size aggregates compared with wild-type cells. In the in vivo model, PLCgamma2-/- 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 Galphaq-/- mice in both levels of injury.


CONCLUSIONS
These results demonstrate that signaling through PLCgamma2 plays an important role in arterial thrombosis, but that its contribution depends on the severity of the vascular lesion.
Nonne
Christelle
C
INSERM U.311, Etablissement Français du Sang-Alsace, Strasbourg, France.
Lenain
Nadège
N
Hechler
Béatrice
B
Mangin
Pierre
P
Cazenave
Jean-Pierre
JP
Gachet
Christian
C
Lanza
François
F
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000201:enzymology*; D003094:Collagen; D004195:Disease Models, Animal; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D007834:Lasers; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010477:Perfusion; D051966:Phospholipase C gamma / Q000235:genetics* / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
D003094:Collagen; D051966:Phospholipase C gamma; D043802:GTP-Binding Protein alpha Subunits, Gq-G11