The Vascular Biology Section of the Cancer and Inflammation Program (CIP) seeks to elucidate the mechanisms that govern blood vessel formation and vascular homeostasis. A healthy vasculature is crucial to our survival. It delivers oxygen and nutrients to every tissue in the body, and at the same time removes waste and allows immune surveillance. Not surprisingly, vascular dysfunction is linked to diverse disorders, from cancer to heart failure. Vascular networks form to satisfy the metabolic demands of tissue growth during development. When we reach adulthood, the vascular endothelium becomes quiescent. However, under disease conditions, this delicate balance is disturbed and endothelium is reactivated. What distinguishes physiological from pathological angiogenesis in diseases is an important question. It has significant implications for therapeutic interventions. We propose that inflammation triggers pathological angiogenesis and distinguishes pathological from physiological angiogenesis. Recently, we have demonstrated that Vav1 is a multifunctional protein. The level of Vav1 is very low in quiescent endothelial cells, however the level of Vav1 is strongly induced by various stress conditions including hypoxia, oxidative stress, turbulence flow, aging and irradiation. Importantly, we found that Vav1 is required for HIF-1 activation in vascular responses to ischemic stress. Using the Vav1 floxed mice we generated, we reveal that conditional deletion of Vav1 in vascular endothelium predisposed the mice to sudden death under cardiac ischemia with increased coronary endothelial apoptosis and increased vascular permeability. On the other hand, prolonged elevation of Vav1 strongly induces endothelial cell senescence. Moreover, Vav1 regulates eNOS activation and vascular tone. These findings demonstrate important functions of Vav1 in vascular biology. The Vav family consists of three members in most vertebrate species (Vav1, Vav2, and Vav3). In a profiling study, we found that non-lethal dose of irradiation specifically upregulated the expression of Vav2 in tumor cells while Vav1 was undetectable. As Vav2 activates small RhoGTPase that mediates cytoskeleton rearrangement and cell motility, we showed that the irradiation treatment increased tumor cell invasion. Interestingly, knockdown of Vav2 in these cells blocked irradiation-induced tumor cell invasion. Additionally, we provided compelling evidence demonstrating that NK4 represents a novel type of GEF for Rap1, a member of the Ras family. Importantly, NK4 is induced by inflammatory cytokines. Hence, NK4 may have evolved to allow a distinct pathway to Rap1 activation, specifically tailored to inflammatory conditions, thereby creating a link between inflammation/infection and the activity of small GTPases. Consistent with the role of Rap1 in autoimmune disorders, transgenic expression of NK4 in a mouse model led to the development of autoantibodies and lymphocytic infiltration in salivary glands similar to those in SS patients. Moreover, NK4 was significantly elevated in samples from patients with SS. The serum levels of NK4 positively correlated with patients primary SS (pSS) clinical characterization. It identifies NK4 as a potential therapeutic target for the treatment of autoimmune diseases, the third most common disease class in the United States.
NIH ExPorter
NIH ExPorter