Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1

Feng Chun Ye, David J. Blackbourn, Michael Mengel, Jian Ping Xie, Li Wu Qian, Whitney Greene, I. Tien Yeh, David Graham, Shou Jiang Gao

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of Kaposi's sarcoma (KS), a highly inflammatory angiogenic tumor of endothelial cells commonly found in untreated AIDS patients. Angiopoietin 2 (Ang-2) modulates the vasculature during inflammation and angiogenesis, but the mechanism by which KSHV regulates Ang-2 expression has not been investigated. Here, we show that KSHV infection of primary human umbilical vein endothelial cells induced the expression and release of Ang-2, which in turn was required for KSHV-induced paracrine-dependent angiogenesis in vivo. Ang-2 was strongly expressed in small vessels and spindle tumor cells in KS tumors. Mechanistically, KSHV activated the Ang-2 promoter via AP-1 and Ets1 transcriptional factors, which were mediated by ERK, JNK, and p38 mitogen-activated protein kinase (MAPK) pathways. Our findings demonstrate the importance of Ang-2 in KS angiogenesis and define a novel role for AP-1 and MAPK pathways in regulating angiogenesis. This study also illustrates a distinct mechanism by which a tumor virus modulates vasculature to promote tumorigenesis and exemplifies the convergence of oncogenesis and angiogenesis pathways in tumor development.

Original languageEnglish (US)
Pages (from-to)3980-3991
Number of pages12
JournalJournal of virology
Volume81
Issue number8
DOIs
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Ye, F. C., Blackbourn, D. J., Mengel, M., Xie, J. P., Qian, L. W., Greene, W., Yeh, I. T., Graham, D., & Gao, S. J. (2007). Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1. Journal of virology, 81(8), 3980-3991. https://doi.org/10.1128/JVI.02089-06