Corneal avascularity is due to soluble VEGF receptor-1

Abstract

The cornea is one of the few tissues in the body with no blood vessels flowing through it. This blood-vessel-free island is often used to test anti-angiogenic therapies for cancer, arthritis, atherosclerosis, diabetes and other diseases driven by pathological angiogenesis. This lack of blood vessels is remarkable because of the highly vascular nature of the surrounding tissues; doubly remarkable because the cornea has now been found to contain large amounts of the potent angiogenic molecule VEGF-A (vascular endothelial growth factor). This discovery has led to a finding that could be important in terms of drug design: a VEGF-A trap known as soluble VEGFR-1 is also present in the cornea and is singly responsible for the absence of blood vessels there. Intriguingly, the few known organisms that have a vascularized cornea (manatees, mutant mice, and some aniridia patients with Pax6 mutations) are all deficient in corneal soluble VEGFR-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 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.