Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth

Romulo J C Albuquerque, Takahiko Hayashi, Won Gil Cho, Mark E. Kleinman, Sami Dridi, Atsunobu Takeda, Judit Z. Baffi, Kiyoshi Yamada, Hiroki Kaneko, Martha G. Green, Joe Chappell, Jörg Wilting, Herbert A. Weich, Satoru Yamagami, Shiro Amano, Nobuhisa Mizuki, Jonathan S. Alexander, Martha L. Peterson, Rolf A. Brekken, Masanori HirashimaSeema Capoor, Tomohiko Usui, Balamurali K. Ambati, Jayakrishna Ambati

Research output: Contribution to journalArticle

256 Scopus citations

Abstract

Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema.

Original languageEnglish (US)
Pages (from-to)1023-1030
Number of pages8
JournalNature medicine
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Albuquerque, R. J. C., Hayashi, T., Cho, W. G., Kleinman, M. E., Dridi, S., Takeda, A., Baffi, J. Z., Yamada, K., Kaneko, H., Green, M. G., Chappell, J., Wilting, J., Weich, H. A., Yamagami, S., Amano, S., Mizuki, N., Alexander, J. S., Peterson, M. L., Brekken, R. A., ... Ambati, J. (2009). Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nature medicine, 15(9), 1023-1030. https://doi.org/10.1038/nm.2018