Vascular Biology Section

癌症和炎症计划(CIP)的血管生物学部分试图阐明管理血管形成和血管内稳态的机制。健康的血管系统对我们的生存至关重要。它将氧气和营养物质输送到身体的每一个组织，同时清除废物，并允许免疫监视。毫不奇怪，血管功能障碍与从癌症到心力衰竭的各种疾病有关。血管网络的形成是为了满足组织发育过程中的代谢需求。当我们成年时，血管内皮细胞就会静止。然而，在疾病条件下，这种微妙的平衡被打破，内皮重新激活。如何区分疾病中的生理性和病理性血管生成是一个重要的问题。这对治疗干预具有重要意义。我们认为炎症触发病理性血管生成，并区分病理性血管生成和生理性血管生成。最近，我们证明了Vav1是一种多功能蛋白质。在静止的内皮细胞中，Vav1的水平很低，但Vav1的水平受到各种应激条件的强烈诱导，包括缺氧、氧化应激、湍流、衰老和辐射。重要的是，我们发现在血管对缺血应激的反应中，Vav1是HIF-1激活所必需的。利用我们建立的Vav1系小鼠，我们发现血管内皮细胞中Vav1的条件性缺失使小鼠在心脏缺血时猝死，冠状动脉内皮细胞凋亡增加，血管通透性增加。另一方面，Vav1的持续升高强烈地诱导内皮细胞衰老。此外，Vav1还调节eNOS的激活和血管张力。这些发现证明了Vav1在血管生物学中的重要功能。Vav家族在大多数脊椎动物中由三个成员组成(Vav1、Vav2和Vav3)。在一项图谱研究中，我们发现非致命性剂量的辐射特异性地上调了肿瘤细胞中Vav2的表达，而Vav1则无法检测到。由于Vav2激活了介导细胞骨架重排和细胞运动的小RhoGTP酶，我们发现放射治疗增加了肿瘤细胞的侵袭性。有趣的是，这些细胞中Vav2基因的敲除阻止了辐射诱导的肿瘤细胞侵袭。此外，我们提供了令人信服的证据表明，对于RAS家族成员Rap1来说，NK4代表了一种新型的全环基金。重要的是，NK4是由炎性细胞因子诱导的。因此，NK4可能已经进化到允许一条不同的途径来激活Rap1，这是专门针对炎症条件定制的，从而在炎症/感染和小GTP酶活性之间建立了联系。与Rap1在自身免疫疾病中的作用一致，在小鼠模型中转基因表达NK4导致了唾液腺中自身抗体的产生和淋巴细胞的渗透，类似于SS患者。此外，SS患者的样本中NK4显著升高。血清NK4水平与PSS患者的临床特征呈正相关。它将NK4确定为治疗自身免疫性疾病的潜在治疗靶点，自身免疫性疾病是美国第三种最常见的疾病。

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.