VEGFs in Artery-Vein Imbalance in AIDS-Kaposi Sarcoma

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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.