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 disorders1-4. But the molecular underpinnings of the avascular phenotype have until now remained obscure5-10 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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Cancer is ubiquitous in wildlife, affecting animals from bivalves to pachyderms and cetaceans. Reports of increasing frequency demonstrate that neoplasia is associated with substantial mortality in wildlife species. Anthropogenic activities and global weather changes are shaping new geographical limitations for many species, and alterations in living niches are associated with visible examples of genetic bottlenecks, toxin exposures, oncogenic pathogens, stress and immunosuppression, which can all contribute to cancers in wild species. Nations that devote resources to monitoring the health of wildlife often do so for human-centric reasons, including for the prediction of the potential for zoonotic disease, shared contaminants, chemicals and medications, and for observing the effect of exposure from crowding and loss of habitat. Given the increasing human footprint on land and in the sea, wildlife conservation should also become a more important motivating factor. Greater attention to the patterns of the emergence of wildlife cancer is imperative because growing numbers of species are existing at the interface between humans and the environment, making wildlife sentinels for both animal and human health. Therefore, monitoring wildlife cancers could offer interesting and novel insights into potentially unique non-age-related mechanisms of carcinogenesis across species.

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