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 journalArticlepeer-review

302 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
Pages (from-to)1023-1030
Number of pages8
JournalNature Medicine
Volume15
Issue number9
DOIs
StatePublished - Sep 2009

Bibliographical note

Funding Information:
We thank R. Ashery-Padan (Tel Aviv University), P. Gruss (Max Planck Institute) and D.C. Beebe (Washington University) for LeCre mice, R.K. Nordeen (University of Colorado) for Cre plasmid, K. Miyazono (University of Tokyo) for pVegf-c and J.L. Arbiser (Emory University) and C.D. Kontos (Duke University) for endothelial cell lines; R. King, L. Xu, M. McConnell, K. Emerson, A. Blanford, M. Baker, S. Furlow, M. LaFalce and C. Long for technical assistance; and R. Mohan, F. Cambi, S. Bondada, M. Detmar, M.W. Fannon, T.V. Getchell, R.K. Jain, T.S. Khurana, B.J. Raisler, J.E. Springer, P.A. Pearson, C.W. Vander Kooi, J.G. Woodward, A.M. Rao, G.S. Rao, K. Ambati and L. Garcia for valuable discussions. This work was supported by US National Institutes of Health and National Eye Institute grants EY015422, EY018350 and EY018836 to J.A. and EY017182 and EY017950 to B.K.A.; a Research to Prevent Blindness Lew R. Wassermann Merit Award (J.A.); Physician Scientist Awards (J.A., B.K.A.); a Medical Student Fellowship (R.J.C.A.); a departmental unrestricted grant (J.A.); a University of Kentucky University Research Professorship (J.A.); Fight for Sight (R.J.C.A.); Japan Society for the Promotion of Science for Young Scientists (A.T.); a VA Merit Award (B.K.A.); and the US Department of Defense (B.K.A.). J.A. is also supported by the Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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