Adequate vascular responses to hypoxia/ischemia are critical for tissue survival, which is particularly important for vital organs such as the heart and brain. We discovered Vav1 as a key vascular regulator of hypoxia. Vav1 is present at low levels in quiescent endothelial cells and hypoxia upregulates Vav1 through inhibition of protein degradation. Importantly, Vav1 is required for HIF-1alpha induction in vascular endothelium upon hypoxic stress. Mice with Vav1-deficient endothelium fail to activate HIF-1 in the vasculature and are predisposed to heart failure and sudden death under cardiac ischemia with increased coronary endothelial apoptosis and vascular dysfunction. These findings reveal that the regulation of Vav1 by hypoxia is analogous to HIF-1alpha regulation. Both proteins are constitutively produced, allowing for rapid responses when stress occurs. Hypoxia induces Vav1, and Vav1 is required for HIF-1 activation. Together they mediate the vascular response to hypoxia and maintain tissue homeostasis. This finding has broad implications in vascular biology and vascular associated disorders. Aging is the most important risk factor for the development of cardiovascular disorders such as atherosclerosis and hypertension. The reasons for these associations are still unclear, but one process that has been increasingly linked to both aging and the development of vascular pathologies is cellular senescence. We demonstrated that Vav1 levels increase with aging. Risk factors associated with atherosclerosis, such as high cholesterol and turbulence flow also upregulate Vav1. Importantly, prolonged elevation of Vav1 strongly induces the production of ROS and oxidative endothelial senescence, as well as inhibition of the production of NO, a highly versatile molecule in vasculature, likely through Sirt1 mediated deacetylation of p53 and eNOS, respectively. Accordingly, deletion of Vav1 protected the mice from the development of endothelial senescence and hypertension associated with aging. These findings identify Vav1 as a potential therapeutic target for vascular diseases. A swift response to hypoxia is a fundamental biological property crucial for the survival of multicellular organisms. The lysosome is a major component of the degradation machinery in mammalian cells, enabling the cells to digest cellular enzymes and regulatory proteins that are no longer needed in order to maintain cellular homeostasis. Interestingly, we discovered that hypoxia inhibits lysosomal activity through suppression of lysosomal acidification/activation via the mTOR/TFEB/vacuolar H+-ATPase pathway. As receptors commonly undergo degradation in lysosomes after activation, hypoxia blocks the degradation and results in increased signaling. There is a positive correlation of hypoxia with RTK receptor levels in tumors. This novel and fundamental finding linking hypoxia to lysosomal activity may provide a molecular explanation for the observation that hypoxic tumors are often aggressive and resistant to therapy. In a profiling study of human endothelial cells, we identified the intracellular NK4 protein as a positive mediator that propagates vascular inflammation. NK4 was originally cloned from the NK cells, but was rediscovered years later and renamed IL-32 although it shares no structural similarity with any known interleukin nor does it have a secretory signal peptide. Despite attempts by multiple groups, no cell surface receptor has been detected for IL-32/NK4. Recently, we provided compelling evidence demonstrating that NK4/IL-32 is actually a GEF for Rap1, a molecule with high homology to Ras. NK4 represents a novel type of GEF that is induced by inflammation and infection, thereby linking inflammation/infection with the activity of small GTPases. Furthermore, NK4 is significantly elevated in samples from patients with Sjogren's Syndrome (SS). The serum levels of NK4 are positively correlated with the clinical characteristics of the disease, and transgenic expression of NK4 in mice activated B cells and resulted in the development of autoimmune phenotypes that resemble the SS patients. In addition, NK4 levels are elevated in patients with B cell lymphoma. Approximately 25% of NK4 transgenic mice also developed B cell lymphoma after one year of age. These findings are consistent with patient data that some autoimmune diseases such as Sjogren's Syndrome have been linked with increased risk of Non-Hodgkin's lymphoma.
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