Analysis of vascular endothelial growth factor : receptor functions in gene-targeted mice

Blood and lymphatic vessels form extensive networks, which deliver oxygen and nutrients to the tissues and remove extravasated fluid. Malfunction of this vasculature results in various diseases such as tumors and ischemic and inflammatory diseases and lymphedema. The molecular mechanism by which vascular endothelial receptors (VEGFRs) control vessel growth and function in physiological and pathological settings is under intensive study, but questions remain. This study aimed to clarify how angiogenesis, the growth of new blood vessels, is regulated by the VEGFRs and by the Notch signaling pathway; moreover if VEGFR-3 is involved in vascular permeability. The purpose was also to understand the role of VEGF-C in embryonic development better. Our first study showed that VEGFR-2 could to sustain angiogenesis to some extent and that postnatal angiogenesis requires VEGFR-2 signaling also in the absence of VEGFR-3. We found that VEGFR-2 is a requirement for endothelial Dll4 upregulation and filopodia formation following Notch inhibition, both independently of VEGFR-3. Then, based on our earlier published findings, we further elucidate the role of VEGFR-3 in blood endothelial cells, using principally a genetic approach. Our data showed that VEGFR-3 loss-of-function is accompanied by increased vascular leakage in the retina, in solid tumors, and in the ear skin. Our third study showed that when all VEGFRs receptors are deleted, the organ-specificity and -sensitivity differ in different vascular beds. BECs. In our fourth study, we discovered that VEGF-C, the ligand for VEGFR-2 and VEGFR-3, which has been known to be a major lymphangiogenic factor now reveals its a unique role in embryonic erythropoiesis but not in adults. This study also showed that VEGF-C regulates the liver colonization of erythro-myeloid progenitors. In sum, these results provide new insights into the treatment of angiogenesis-related diseases, such as cancer. Elucidation of this mechanism is essential for the therapeutic manipulation of these pathologies, and in the future, more than 500 million people worldwide may benefit from pro- or anti-angiogenesis treatment.