The essential roles of HIF-1alpha and VHL in endothelial cells during development and solid tumor formation.

摘要

In addition to its role as a selective permeability barrier for blood vessels, the vascular endothelial cell reacts with physical and chemical stimuli within the blood circulation and plays a key role in many physiological and pathological processes. This dissertation focuses on understanding how endothelial cells respond to local microenvironment during vasculogenesis and angiogenesis.;Hypoxic conditions can profoundly affect the functions of endothelial cells. It has been well shown that HIF-1 acts as a master regulator for hypoxic responses. So in the second chapter of this dissertation, I investigated the role of HIF-1alpha in endothelial cells. This dissertation has demonstrated that HIF-1alpha is critical for tumor and wound angiogenesis by regulating the proliferation, migration and capillary-like tube formation of endothelial cells under hypoxic conditions. HIF-1alpha plays a key role in endothelial cell hypoxic responses by regulating hypoxia-induced endothelial autocrine VEGF.;pVHL has been shown to be important in placental vasculogenesis during development. In the third chapter of this dissertation, I investigated the role of pVHL during vessel development. This dissertation has shown that independent of its E3 ligase function in regulating hypoxic responses, pVHL also plays a critical role in regulating endothelial extracellular matrix assembly. The dissertation has demonstrated that endothelial pVHL is essential for the development of extraembryonic and embryonic endothelium by regulating the structure of vessel fibronectin matrix.