Article abstract
Nature Medicine 15, 1023 - 1030 (2009)
Published online: 9 August 2009 | doi:10.1038/nm.2018
Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth
Romulo J C Albuquerque1,2, Takahiko Hayashi3,14, Won Gil Cho1,14, Mark E Kleinman1,14, Sami Dridi1, Atsunobu Takeda1, Judit Z Baffi1, Kiyoshi Yamada1, Hiroki Kaneko1, Martha G Green1, Joe Chappell4, Jörg Wilting5, Herbert A Weich6, Satoru Yamagami7, Shiro Amano7, Nobuhisa Mizuki3, Jonathan S Alexander8, Martha L Peterson9, Rolf A Brekken10, Masanori Hirashima11, Seema Capoor1, Tomohiko Usui7, Balamurali K Ambati12,13 & Jayakrishna Ambati1,2
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)
- Departments of Ophthalmology & Visual Sciences, Lexington, Kentucky, USA.
- Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
- Department of Ophthalmology, Yokohama City University, Yokohama, Japan.
- Department of Plant & Soil Sciences, University of Kentucky, Lexington, Kentucky, USA.
- Department of Anatomy and Cell Biology, Georg-August-University, Goettingen, Germany.
- Department Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
- Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA.
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.
- Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA.
- These authors contributed equally to this work.
Correspondence to: Jayakrishna Ambati1,2 e-mail: jamba2@email.uky.edu
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