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Letter

Nature 443, 993-997 (26 October 2006) | doi:10.1038/nature05249; Received 19 June 2006; Accepted 15 September 2006; Published online 18 October 2006

Corneal avascularity is due to soluble VEGF receptor-1

Balamurali K. Ambati1,2, Miho Nozaki3, Nirbhai Singh1, Atsunobu Takeda3, Pooja D. Jani1, Tushar Suthar1, Romulo J. C. Albuquerque3, Elizabeth Richter1, Eiji Sakurai3,6, Michael T. Newcomb3, Mark E. Kleinman3, Ruth B. Caldwell2, Qing Lin7, Yuichiro Ogura6, Angela Orecchia8, Don A. Samuelson9, Dalen W. Agnew10,21, Judy St. Leger11, W. Richard Green12, Parameshwar J. Mahasreshti13, David T. Curiel13, Donna Kwan14, Helene Marsh14, Sakae Ikeda15, Lucy J. Leiper16, J. Martin Collinson16, Sasha Bogdanovich17, Tejvir S. Khurana17, Masabumi Shibuya18, Megan E. Baldwin19, Napoleone Ferrara19, Hans-Peter Gerber19,21, Sandro De Falco20, Jassir Witta4, Judit Z. Baffi3, Brian J. Raisler3,5 & Jayakrishna Ambati3,5

  1. Departments of Ophthalmology and
  2. Cell Biology, Medical College of Georgia & Augusta Veterans Affairs Medical Center, Augusta, Georgia 30907, USA
  3. Departments of Ophthalmology & Visual Sciences,
  4. Internal Medicine and
  5. Physiology, University of Kentucky, Lexington, Kentucky 40506, USA
  6. Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601, Japan
  7. Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennesee 37232, USA
  8. Molecular and Cell Biology Laboratory, IDI-IRCCS, Rome 00167, Italy
  9. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Gainesville, Florida 32610, USA
  10. Department of Pathology, Microbiology and Immunology, University of California, Davis, California 95616, USA
  11. Department of Pathology, Sea World, San Diego, California 92109, USA
  12. The Eye Pathology Laboratory, Wilmer Institute and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA
  13. Division of Human Gene Therapy, The Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
  14. School of Tropical Environment Studies and Geography, James Cook University, Townsville, Queensland 4811, Australia
  15. Department of Medical Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA
  16. School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
  17. Department of Physiology & Pennsylvania Muscle Institute, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
  18. Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  19. Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080, USA
  20. Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Naples 80131, Italy
  21. Present addresses: Diagnostic Center for Population and Animal Health, Michigan State University, Lansing, Michigan 48910, USA (D.W.A.); Department of Translational Biology, Seattle Genetics, Bothell, Washington 98021, USA (H.-P.G.).

Correspondence to: Jayakrishna Ambati3,5 Correspondence and requests for materials should be addressed to B.K.A. (Email: bambati@mail.mcg.edu) or J.A. (Email: jamba2@uky.edu).

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Corneal avascularity—the absence of blood vessels in the cornea—is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders1, 2, 3, 4. But the molecular underpinnings of the avascular phenotype have until now remained obscure5, 6, 7, 8, 9, 10 and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap11 by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice12, 13 and Pax6+/- patients with aniridia14 are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas15, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.