Kurzfassung

Venous thromboembolism is a leading cause of morbidity and mortality, especially in elderly people. Endothelial cell dysfunction constitutes a major risk factor, in addition to alterations in blood flow and coagulation. Increased expression of p53 has been implicated in the development of vascular senescence, i.e. age-associated changes in the cardiovascular system, and preliminary data support a role for p53 in the regulation of endothelial (dys-) function. The aim of this project is to...Venous thromboembolism is a leading cause of morbidity and mortality, especially in elderly people. Endothelial cell dysfunction constitutes a major risk factor, in addition to alterations in blood flow and coagulation. Increased expression of p53 has been implicated in the development of vascular senescence, i.e. age-associated changes in the cardiovascular system, and preliminary data support a role for p53 in the regulation of endothelial (dys-) function. The aim of this project is to determine the importance of endothelial apoptosis and p53 expression for deep vein thrombosis and thus, whether vascular senescence and increased levels of endothelial p53 are causally involved in the exponential increase of venous thromboembolism with age. To address these questions, a genetically modified mouse model with an endothelium-specific, conditional p53 deletion will be used and subjected to subtotal ligation of the Vena cava inferior to induce venous thrombosis, followed by serial non-invasive image analysis over three weeks as well as histochemical and molecular analysis of vein tissues after sacrifice. Moreover, mice will be intravenously injected with a mixture of collagen and epinephrine to induce intravascular platelet aggregation and pulmonary thromboembolisation. In addition, we plan to translate our experimental findings and to study whether circulating markers of endothelial cell apoptosis (i.e. circulating endothelial cells) may be useful as biomarkers for the risk and severity of venous thromboembolism in humans. In summary, we expect that our studies will clarify whether and how age and endothelial p53 affect the course and severity of venous thrombus formation.» weiterlesen» einklappen