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Corneal avascularity is due to soluble VEGF receptor-1

Nature volume 443, pages 993–997 (2006)Cite this article

Abstract

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.

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Figure 1: Avascular cornea contains sflt-1 bound to VEGF-A.
Figure 2: Topical enzymatically active Cre recombinase abolishes corneal avascularity in flt-1 loxP/loxP mice.
Figure 3: Knockdown of sflt-1 mRNA abolishes corneal avascularity.
Figure 4: Spontaneously vascularized corneas lacking sflt-1 are rescued by sflt-1 administration.

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Acknowledgements

We thank the various aquaria, zoos and wildlife rehabilitation centres that donated tissues for comparative studies; R. Groom, S. Joshi, M. Kellogg, R. King, C. K. Lau, P. Lewis, N. Mezei, K.K. Smith and L. Xu for technical assistance; R. J. Kryscio for statistical guidance; and R. Mohan, S. Bondada, M. W. Fannon, L. Mazzaro, Y. Nozaki, P. A. Pearson, L. Peichl, A. M. Rao, G. S. Rao and K. Ambati for discussions. J.A. was supported by the NEI/NIH, the Lew R. Wasserman Merit Award (Research to Prevent Blindness), the Dennis W. Jahnigen Career Development Award (American Geriatrics Society, John A. Hartford Foundation, Atlantic Philanthropies), the Macula Vision Research Foundation, the International Retinal Research Foundation, the E. Matilda Ziegler Foundation for the Blind, the Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, a physician–scientist award from University of Kentucky, and a departmental challenge grant from Research to Prevent Blindness; M.N. by ARVO/Japan National Society for the Prevention of Blindness; E.S. by Fight For Sight; R.J.C.A by Research to Prevent Blindness; J.Z.B. and B.R. by the NIDCD/NIH; A.T. by a Japan Young Scientist Award; B.K.A. by a VA Career Development Award, the Knights-Templar Eye Foundation and Fight for Sight; N.S by ARVO/Alcon; S.I. by the NEI/NIH; J.M.C. by the Wellcome Trust and the Birth Defects Foundation; T.S.K by the NEI/NIH and the NIAMS/NIH; S.B. by the Muscular Dystrophy Association; and S.D.F. by the AIRC (Italian Association for Cancer Research). Author Contributions B.K.A. and J.A. conceived and designed the experiments, wrote the manuscript, and are joint senior authors. M.N., N.S., A.T., P.D.J., J.Z.B. and B.J.R. contributed equally.

Author information

Author notes

  1. Dalen W. Agnew

    Present address: Diagnostic Center for Population and Animal Health, Michigan State University, Lansing, Michigan, 48910, USA

  2. Hans-Peter Gerber

    Present address: Department of Translational Biology, Seattle Genetics, Bothell, Washington, 98021, USA

Authors and Affiliations

  1. Departments of Ophthalmology and,

    Balamurali K. Ambati, Nirbhai Singh, Pooja D. Jani, Tushar Suthar & Elizabeth Richter

  2. Cell Biology, Medical College of Georgia & Augusta Veterans Affairs Medical Center, Augusta, Georgia, 30907, USA

    Balamurali K. Ambati & Ruth B. Caldwell

  3. Departments of Ophthalmology & Visual Sciences,

    Miho Nozaki, Atsunobu Takeda, Romulo J. C. Albuquerque, Eiji Sakurai, Michael T. Newcomb, Mark E. Kleinman, Judit Z. Baffi, Brian J. Raisler & Jayakrishna Ambati

  4. Internal Medicine and,

    Jassir Witta

  5. Physiology, University of Kentucky, Lexington, Kentucky, 40506, USA

    Brian J. Raisler & Jayakrishna Ambati

  6. Department of Ophthalmology, Nagoya City University Medical School, Nagoya, 467-8601, Japan

    Eiji Sakurai & Yuichiro Ogura

  7. Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennesee, 37232, USA

    Qing Lin

  8. Molecular and Cell Biology Laboratory, IDI-IRCCS, Rome, 00167, Italy

    Angela Orecchia

  9. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Gainesville, Florida, 32610, USA

    Don A. Samuelson

  10. Department of Pathology, Microbiology and Immunology, University of California, Davis, California, 95616, USA

    Dalen W. Agnew

  11. Department of Pathology, Sea World, San Diego, California, 92109, USA

    Judy St. Leger

  12. The Eye Pathology Laboratory, Wilmer Institute and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, 21205, USA

    W. Richard Green

  13. Division of Human Gene Therapy, The Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Parameshwar J. Mahasreshti & David T. Curiel

  14. School of Tropical Environment Studies and Geography, James Cook University, Townsville, Queensland, 4811, Australia

    Donna Kwan & Helene Marsh

  15. Department of Medical Genetics, University of Wisconsin, Madison, Wisconsin, 53706, USA

    Sakae Ikeda

  16. School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK

    Lucy J. Leiper & J. Martin Collinson

  17. Department of Physiology & Pennsylvania Muscle Institute, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Sasha Bogdanovich & Tejvir S. Khurana

  18. Institute of Medical Science, University of Tokyo, 108-8639, Tokyo, Japan

    Masabumi Shibuya

  19. Department of Molecular Oncology, Genentech Inc., South San Francisco, California, 94080, USA

    Megan E. Baldwin, Napoleone Ferrara & Hans-Peter Gerber

  20. Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Naples, 80131, Italy

    Sandro De Falco

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Correspondence to Jayakrishna Ambati.

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Competing interests

B.K.A, J.A. and N.S. are listed as inventors on a patent application describing these findings.

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Ambati, B., Nozaki, M., Singh, N. et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443, 993–997 (2006). https://doi.org/10.1038/nature05249

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