Molecular Regulation of Arterial Thrombosis

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DESCRIPTION (provided by applicant): The overall goal of this project is to understand the complex regulatory role of the tissue factor pathway in vascular homeostasis. Arterial thrombosis is initiated when endothelial disruption or injury leads to exposure and activation of subendothelial procoagulants, including tissue factor (TF), to flowing blood. We have focused on tissue factor pathway inhibitor (TFPI) as the major physiologic inhibitor of TF. Locally active TFPI at the luminal surface of endothelium provides a nonthrombogenic surface in the unperturbed state. TFPI, a Kunitz-type serine-protease inhibitor, uniquely modifies the coagulation cascade in vivo by binding to TF-factor Vila (via the K1 domain) and factor Xa (via the K2 domain) forming an inhibitory complex which dampens further coagulation. However, if local levels of TFPI are not adequate to dampen local TF activity, thrombosis continues. TFPI, via proposed direct effects and indirectly via its anticoagulant properties, also influences vascular structure. Our objective is to define the role of the endothelium in this process. Locally active TFPI may be derived from vascular cells or from the circulation. Endothelial cells may play at least two roles in these processes: as a site of TFPI action and as an accessible source of local and circulating forms. These functions may vary in distinct vascular beds. Recent clinical studies indicate an association between low circulating TFPI levels and increased vascular risk. The focus of this proposal is to delineate the role of endothelial-derived TFPI in regulating the homeostatic balance between TF and TFPI and its resultant effects on macro- and micro-vascular structure, function and thrombosis in multiple vascular beds. Our underlying hypothesis is that endothelial production of TFPI regulates circulating and local TFPI levels which modulate micro- and macro-vascular function and thrombosis during development and in adults. Three specific aims are proposed. Specific Aim 1: To determine the effects of endothelial-specific gene deletion of TFPI on murine development and hemostasis. Specific Aim 2: To define the role of endothelial-derived TFPI on vascular thrombosis. Specific Aim 3: To define the role of endothelial-derived TFPI on vascular remodeling including angiogenesis.