Given the ongoing role of VEGFA for maintenance of the retinal vasculature, are there alternative strategies to treating vascular diseases of the eye? In their paper, Kurihara and colleagues also deleted hypoxia inducible factor 1 α (Hif1a
) and hypoxia inducible factor 2 α (Epas1
) from RPE cells (8
). HIFs are basic-helix-loop helix transcription factors that regulate VEGFA production, and similar to VEGFA, their expression is upregulated in retinal diseases. In contrast to VEGF deletion, loss of Hif1a
did not cause vision loss or endothelial damage in mice. However, elimination of these factors rescued pathologic angiogenesis in the laser photocoagulation model of choroidal neovascularization. The authors suggest that Hifs may be a more desirable target in eye disease, shutting down pathologic angiogenesis without damaging healthy vessels, perhaps by more modest regulation of endogenous VEGFA levels. Nonetheless, feasibility of this approach in patients and/or experimental models must be established. Although VEGFA is one of the best-known targets of the HIF pathway, endogenous levels of Vegfa were preserved in the RPE-Hif
–knockout mice. This suggests a dominant role for Hif-independent regulation of Vegfa or perhaps that actual deletion of the Hif allele(s) was lower than the 68% efficiency rate suggested by experiments in reporter mice (8
). Combination angiostatic therapies, which include induction with an anti-VEGF agent and maintenance with a non-VEGF agent with angiostatic properties, is another possibility (17
This study demonstrates an important functional role for Vegfa in supporting the adult subretinal vasculature, including the choriocapillaris, which is particularly important for nurturing the cone photoreceptors and maintaining central vision. This is the first documentation for a critical impact of Vegfa on the mammalian adult retina and should send a note of caution to clinicians who are treating patients with anti-VEGF agents for retinal disease. It will be important to carefully screen treated patients for detrimental long-term effects of VEGF knockdown on their vision. Future studies to identify susceptibility factors for anti-VEGF toxicities in eye and other organs are also needed.