Corneal avascularity is due to soluble VEGF receptor-1

Balamurali K. Ambati, Miho Nozaki, Nirbhai Singh, Atsunobu Takeda, Pooja D. Jani, Tushar Suthar, Romulo J.C. Albuquerque, Elizabeth Richter, Eiji Sakurai, Michael T. Newcomb, Mark E. Kleinman, Ruth B. Caldwell, Qing Lin, Yuichiro Ogura, Angela Orecchia, Don A. Samuelson, Dalen W. Agnew, Judy St. Leger, W. Richard Green, Parameshwar J. MahasreshtiDavid T. Curiel, Donna Kwan, Helene Marsh, Sakae Ikeda, Lucy J. Leiper, J. Martin Collinson, Sasha Bogdanovich, Tejvir S. Khurana, Masabumi Shibuya, Megan E. Baldwin, Napoleone Ferrara, Hans Peter Gerber, Sandro De Falco, Jassir Witta, Judit Z. Baffi, Brian J. Raisler, Jayakrishna Ambati

Research output: Contribution to journalArticle

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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 disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure 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 trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia 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 corneas, 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.

Original languageEnglish (US)
Pages (from-to)993-997
Number of pages5
JournalNature
Volume443
Issue number7114
DOIs
StatePublished - Oct 26 2006

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    Ambati, B. K., Nozaki, M., Singh, N., Takeda, A., Jani, P. D., Suthar, T., Albuquerque, R. J. C., Richter, E., Sakurai, E., Newcomb, M. T., Kleinman, M. E., Caldwell, R. B., Lin, Q., Ogura, Y., Orecchia, A., Samuelson, D. A., Agnew, D. W., St. Leger, J., Green, W. R., ... Ambati, J. (2006). Corneal avascularity is due to soluble VEGF receptor-1. Nature, 443(7114), 993-997. https://doi.org/10.1038/nature05249