Regulation of Endothelial Nitric Oxide Synthase by Thrombin

Abstract

Endothelial cells play a pivotal role in the regulation of vascular function. Not only do endothelial cells modulate vascular tone and control the initiation and progression of vascular inflammation through regulated secretion of vasoactive agents and by surface expression of adhesion molecules, but they also provide a hemocompatible vessel lining by molecular control of platelet aggregation, coagulation, and fibrinolysis.1,2 One of the many vasoactive agents important in maintaining both vascular integrity and hemostasis is thrombin, the main effector serine protease of the coagulation cascade.3,4 Physiologically, thrombin is short lived in the circulation, and in the context of a normal endothelium, thrombin activates the protein C system to terminate its own production.2,4 However, in pathological conditions, at sites of vascular injury, thrombin has a host of direct actions. It is a potent activator of platelets, it induces shape and permeability changes of endothelial cells, it mobilizes adhesion molecules to the endothelial surface, it stimulates autocoid and proinflammatory cytokine production, it regulates blood vessel diameter by modulating endothelium-dependent vasodilation and endothelium-independent vascular smooth muscle vasoconstriction, and it stimulates vascular cell growth.1–7 Endothelial effects of thrombin have been attributed to NO production through activation of endothelial NO synthase (eNOS), which requires phosphorylation of Ser1179.8,9 Exact mechanisms whereby thrombin regulates eNOS phosphorylation remain unclear, although Ca2+/calmodulin and Akt have been implicated to be critical. In the current issue of Hypertension , Motley et …