VEGFs in Artery-Vein Imbalance in AIDS-Kaposi Sarcoma

描述(申请人提供)：卡波西肉瘤(KS)发展为血管增殖过程，以应对感染HHV-8的内皮细胞或其前体细胞。KS是一种高度血管性的肿瘤，具有异常的血管结构和红细胞外溢。KS肿瘤细胞表达独特的细胞表面受体，并仅限于血管内皮细胞，如VEGFR-2和VEGFR-3。血管内皮生长因子家族蛋白在KS中高表达，为该肿瘤提供了强大的生长和生存信号。现在已经知道，动脉和静脉内皮细胞是不同的表型，即使在毛细血管床的水平上也是如此。标志这一区别的最重要的细胞表面蛋白是表达在动脉内皮细胞上的ePhin B2及其受体EphB4，它表达在静脉内皮细胞上。任何一种蛋白质的缺乏都会干扰血管的正常成熟。EphB4的诱导与EphB4的诱导相反，诱导的EphB4诱导的血管萌发增多。由于KS的高度血管性质，我们希望确定KS是否揭示了动脉或静脉的标志物，以及它们的表达是否存在失衡。值得注意的是，我们发现了EPhin B2的表达，但没有EphB4的表达。为了了解HHV-8病毒是如何参与这一表型的，我们确定了内皮细胞感染HHV-8病毒后，ewitin B2被诱导表达。此外，HHV-8vGPCR单独作用可诱导EPhin B2和VEGF的表达。众所周知，在发育过程中，血管内皮生长因子本身会诱导EphB4产生EphB4。HHV-8直接或间接诱导KS动脉表型的可能性将在目前的提案中进行调查。我们还确定了血管内皮生长因子-C可以诱导EPhin B2，而其他KS生长因子不能。我们推测EphB4的缺失或减少可能是导致KS血管系统异常的原因。我们认为HHV-8通过病毒蛋白的直接作用或通过细胞自分泌或旁分泌分子的调节来诱导动脉标志物的表达。此外，还将研究血管内皮生长因子和血管内皮细胞生长因子C诱导肾上腺素B2的确切机制。在目前的提案中，我们计划描述KS病变和细胞的动脉和静脉特异性标记物，并研究HHV-8、血管内皮生长因子和血管内皮生长因子C是如何诱导ePhin B2的。这项工作有望加深我们对KS发病机制的理解，为KS的新疗法提供机会，并有助于理解血管生物学。

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) develops as a vascular proliferate process in response to infection of endothelial cells or their precursors with HHV-8. KS is a highly vascular tumor with aberrant vascular structures and extravasated red blood cells. KS tumor cells express cell surface receptors unique and restricted to endothelial cells such as VEGFR-2 and VEGFR-3. The VEGF family of proteins is overexpressed in KS and provides strong growth and survival signals for this tumor. It is now known that arterial and venous endothelial cells are phenotypically distinct, even at the level of the capillary beds. The most significant cell surface proteins which mark this distinction are ephrin B2, expressed on arterial endothelial cells, and its receptor, EphB4, which is expressed on venous endothelial cells. The absence of either protein interferes with proper vessel maturation. Ephrin B2 induction leads to increased sprouting of vessels, whereas the opposite is true for EphB4 induction. Due to the highly vascular nature of KS we wished to determine if KS revealed markers for artery or vein, and if there was an imbalance in their expression. Remarkably, we found expression of ephrin B2, but not EphB4. In order to understand how HHV-8 could participate in this phenotype, we determined that ephrin B2 was induced by HHV-8 infection of endothelial cells. Further, HHV- 8 vGPCR alone could induce ephrin B2 and VEGF. VEGF is known to itself induce ephrin B2 in favor of EphB4 during development. The possibility that HHV-8 directly or indirectly induces the arterial phenotype of KS will be investigated in the current proposal. We have also determined that VEGF-C can induce ephrin B2, while other KS growth factors do not. We hypothesize that absence or reduction of EphB4 may be responsible for the aberrant nature of the KS vasculature. We propose that HHV-8 induces arterial marker expression by the direct effect of viral proteins or by the regulation of cellular autocrine or paracrine molecules. The precise mechanism of ephrin B2 induction through VEGF and VEGF-C will also be studied. In the current proposal we plan to profile KS lesions and cells for arterial and venous specific markers, and study how HHV-8, VEGF and VEGF-C induce ephrin B2. This work is anticipated to enhance our understanding of KS pathogenesis, provide opportunities for novel therapies for KS, and contribute to the understanding of vascular biology.