Corneal avascularity is due to soluble VEGF receptor-1

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(1-4). But the molecular underpinnings of the avascular phenotype have until now remained obscure(5-10) 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 trap(11) 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(12,13) and Pax6(+/-) patients with aniridia(14) 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(15), 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.