VEGFs in Artery-Vein Imbalance in AIDS-Kaposi Sarcoma

描述（由申请人提供）：卡波西肉瘤（KS）是一种血管增生过程，是对内皮细胞或其前体感染HHV-8的反应。KS是一种血管结构异常、红细胞外溢的高度血管性肿瘤。KS肿瘤细胞表达内皮细胞特有的细胞表面受体，如VEGFR-2和VEGFR-3。VEGF家族蛋白在KS中过度表达，并为该肿瘤提供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在表型上是不同的，甚至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在动脉内皮细胞上表达的ephrin B2及其受体EphB4，它在静脉内皮细胞上表达。这两种蛋白的缺失都会干扰正常的血管成熟。Ephrin B2诱导导致血管萌发增加，而EphB4诱导则相反。由于KS的高度血管性，我们希望确定KS是否显示动脉或静脉标记物，以及它们的表达是否存在不平衡。值得注意的是，我们发现ephrin B2表达，而EphB4未表达。为了了解HHV-8如何参与这种表型，我们确定HHV-8感染内皮细胞可诱导ephrin B2。此外，单独使用HHV- 8 vGPCR可诱导ephrin B2和VEGF。已知VEGF本身在发育过程中诱导ephrin B2有利于EphB4。目前的建议将研究HHV-8直接或间接诱导KS动脉表型的可能性。我们还确定VEGF-C可以诱导ephrin B2，而其他KS生长因子则不能。我们假设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调节细胞自分泌或旁分泌分子诱导动脉标志物的表达。通过VEGF和VEGF- c诱导ephrin B2的确切机制也将被研究。在目前的提案中，我们计划分析KS病变和细胞的动脉和静脉特异性标志物，并研究HHV-8， VEGF和VEGF- c如何诱导ephrin B2。这项工作有望增进我们对KS发病机制的理解，为KS的新疗法提供机会，并有助于血管生物学的理解。

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.