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G protein-dependent basal and evoked endothelial cell vWF secretion.
|Title||G protein-dependent basal and evoked endothelial cell vWF secretion.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Rusu L, Andreeva A, Visintine DJ, Kim K, Vogel SM, Stojanovic-Terpo A, Chernaya O, Liu G, Bakhshi FR, Haberichter SL, Iwanari H, Kusano-Arai O, Suzuki N, Hamakubo T, Kozasa T, Cho J, Du X, Minshall RD|
|Date Published||2013 Sep 30|
von Willebrand factor (vWF) secretion by endothelial cells (EC) is essential for hemostasis and thrombosis, however, the molecular mechanisms are poorly understood. Interestingly, we observed increased bleeding in EC-Gα13(-/-);Gα12(-/-) mice that could be normalized by infusion of human vWF. Blood from Gα12(-/-) mice exhibited significantly reduced vWF levels but normal vWF multimers and impaired laser-induced thrombus formation indicating Gα12 plays a prominent role in EC vWF secretion required for hemostasis and thrombosis. In isolated buffer-perfused mouse lungs, basal vWF levels were significantly reduced in Gα12(-/-) whereas thrombin-induced vWF secretion was defective in both EC-Gαq(-/-);Gα11(-/-) and Gα12(-/-) mice. Using siRNA in cultured HUVEC and HPAEC, depletion of Gα12 and α-SNAP (but not Gα13) inhibited both basal and thrombin-induced vWF secretion while over-expression of activated Gα12 promoted vWF secretion. In Gαq, p115 RhoGEF, and RhoA-depleted HUVEC, thrombin-induced vWF secretion was reduced by 40% whereas basal secretion was unchanged. Finally, in vitro binding assays revealed Gα12 N-terminal residues 10-15 mediated the binding of Gα12 to α-SNAP, and an engineered α-SNAP binding-domain minigene peptide blocked basal and evoked vWF secretion. Discovery of obligatory and complementary roles of Gα12 and Gαq/11 in basal vs. evoked EC vWF secretion may provide promising new therapeutic strategies for treatment of thrombotic disease.