Control of tiussue factor expression during the inflammatory and angiogenic response of endothelial cells

The vascular system of the body is lined on its inner surface by endothelial cells. This vascular endothelium is a multifunctional organ which is essential for normal vascular physiology and homeostasis. It controls the exchange of substances, peptides and immune cells between the blood stream and the various tissues of the body and has a pivotal role to maintain an anti-coagulant environment. During wound repair the endothelial cells grow and develop new blood vessels, a process termed angiogenesis. In a pathologic situation, induction of angiogenesis is the prerequisite for the growth of tumours. To fullfil its normal functions EC can initiate several distinct, but overlapping and complex programs. During inflammation EC initiate an immune response resulting in the expression of a number of cell adhesion molecules and cytokines and synthesize prothrombotic proteins such as tissue factor (TF). In a second main program, the angiogenic response, EC initiate the synthesis of proteins necessary for growth and migration of the cells leading to invasion of capillaries into the surrounding tissue. Several lines of evidence suggest a dual role of the cell surface receptor TF during the inflammatory and angiogenic response of EC. It is well established that TF binds factor VII and is the major cellular trigger of the coagulation cascade. As such TF is a main cause of thrombotic events and is linked to dysfunctions of the endothelium during pathological and chronic inflammatory activation. In these situations mechanisms to prevent inappropriate TF expression are lost. Moreover, recent evidence suggests that TF, in addition to its role in induction of blood clotting, can mediate the activation of adhesion and migration of EC and may participate in embryonic blood vessel development and tumour-associated angiogenesis. Accordingly, we have recently shown that TF is strongly upregulated by the angiogenic trigger vascular endothelial cell growth factor (VEGF). The general aim of this project is to investigate the control of TF expression, how pathological TF expression leading to thrombotic events can occur and what its potential role during VEGF induction of the angiogenic process may be. This study will in addition contribute to the major question how EC decide whether to undergo the inflammatory or angiogenic response. We believe that a closer understanding of the distinct mechanisms determining the expression of TF and other proteins during inflammation and angiogenesis will allow the design of strategies to interfere with pathological dysfunctions of EC in regard to acute and chronic inflammations, thromboembolic diseases and cancer.