It is becoming evident that the importance of platelets in animal physiology far exceeds their role in vascularinjury. In this proposal, we will address platelet function in angiogenesis, inflammation and heart disease. Inaddition, we will investigate the role of the metalloproteinase ADAMTS-13 and the effect of elevated procoagulantactivity on vascular function, in particular in the brain. The project will be divided into threeindependent but thematically related Specific Aims.The first specific aim will develop our preliminary observations that platelets play an important role inangiogenesis by preventing hemorrhage. In collaboration with Project V (Hynes), we will test the hypothesisthat platelet adhesion through adhesion receptors is required for angiogenesis. We will visualize plateletinteractions with angiogenic vessels by multiphoton microscopy and study angiogenesis in mice mutant invarious adhesion molecules. The role of platelet secretion in vessel stabilization will also be addressed.The second specific aim will study the pro-inflammatory functions of platelets and, with Project I (Krieger), therole of platelets in severe heart disease and atherosclerosis. We have observed that the presence of activatedplatelets in circulation, such as may occur in surgical patients, systemically activates endothelium andincreases P-selectin expression. This is reflected in enhanced leukocyte rolling on the vessel wall. Themolecular mechanisms of this new inflammatory platelet function will be explored. Knowing the role of plateletsin inflammation, we were surprised to observe that in advanced heart disease, such as seen in the mousemodels developed in Project I, platelet function had a protective effect on the animals. We hypothesize thatplatelets are crucial to prevent hemorrhage in the diseased heart, thus preventing excessive fibrosis of theorgan. Fibrin deposition in the lesions was drastically reduced in the absence of platelets, indicating thatplatelets may be required for localized coagulation to occur. We will address this experimentally.The last aim will examine the consequences of pro-coagulant and pro-thrombotic conditions on blood vesselfunction. We have preliminary results that indicate that high levels of pro-coagulant microparticles in ananimal's plasma lead to a breakdown of the endothelial blood-brain barrier. We hypothesize that this involvesexcessive thrombin generation/fibrin deposition resulting in signaling leading to vascular permeability. Theproposed molecular mechanism will be studied. We have also begun analysis of mice lacking ADAMTS-13, amouse model of thrombotic thrombocytopenic purpura (TTP). We will evaluate the role of this enzyme inplatelet adhesion to endothelium and in thrombotic models.Project II will further collaborate with Project III (Lodish) on the role of adiponectin and T-cadherin inthrombosis and atherosclerosis.
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