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

Nature Medicine volume 15, pages 1023–1030 (2009)Cite this article

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 (pages 993–994)

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Figure 1: Loss of endogenous sVegfr-2, which antagonizes Vegf-c, leads to spontaneous corneal lymphangiogenesis.
Figure 2: sVegfr-2 inhibits reparative corneal lymphangiogenesis and rejection of corneal allografts.
Figure 3: Endogenous Vegf-c and sVegfr-2 selectively modulate corneal lymphangiogenesis.
Figure 4: Loss of sVegfr2 in the skin induces lymphatic hyperplasia.
Figure 5: sVegfr-2 is produced by BECs and skin epithelium and circulates in plasma.
Figure 6: sVEGFR-2 exists in humans and inhibits human lymphangioma cell proliferation.

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Acknowledgements

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.

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Author notes

  1. Takahiko Hayashi, Won Gil Cho and Mark E Kleinman: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Ophthalmology & Visual Sciences, Lexington, Kentucky, USA

    Romulo J C Albuquerque, Won Gil Cho, Mark E Kleinman, Sami Dridi, Atsunobu Takeda, Judit Z Baffi, Kiyoshi Yamada, Hiroki Kaneko, Martha G Green, Seema Capoor & Jayakrishna Ambati

  2. Department of Physiology, University of Kentucky, Lexington, Kentucky, USA

    Romulo J C Albuquerque & Jayakrishna Ambati

  3. Department of Ophthalmology, Yokohama City University, Yokohama, Japan

    Takahiko Hayashi & Nobuhisa Mizuki

  4. Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky, USA

    Joe Chappell

  5. Department of Anatomy and Cell Biology, Georg-August-University, Goettingen, Germany

    Jörg Wilting

  6. Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany

    Herbert A Weich

  7. Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan

    Satoru Yamagami, Shiro Amano & Tomohiko Usui

  8. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA

    Jonathan S Alexander

  9. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA

    Martha L Peterson

  10. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Rolf A Brekken

  11. Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan

    Masanori Hirashima

  12. Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Balamurali K Ambati

  13. Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA

    Balamurali K Ambati

Authors
  1. Romulo J C Albuquerque
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Contributions

R.J.C.A., T.H., W.G.C., M.E.K., S.D., A.T., J.Z.B., K.Y., H.K., M.G.G. and S.C. designed and conducted experiments. R.A.B., J.W., H.A.W. and J.S.A. provided reagents and, with J.C., S.Y., S.A., N.M., M.L.P., M.H., T.U. and B.K.A., participated in planning experiments. J.A. conceived of and directed the project. R.J.C.A. and J.A. wrote the manuscript. All authors had the opportunity to discuss the results and comment on the manuscript.

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Correspondence to Jayakrishna Ambati.

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J.A. and R.J.C.A. are named as inventors in a patent application to the US Patent and Trademark Office filed by the University of Kentucky surrounding the intellectual property described in this paper (gene and protein sequences and therapeutic application of augmenting or diminishing soluble vascular endothelial growth factor receptor-2 amounts). As employees of the University of Kentucky, they are covered under the distribution of royalties policies of the institution.

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Albuquerque, R., Hayashi, T., Cho, W. et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 15, 1023–1030 (2009). https://doi.org/10.1038/nm.2018

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