Semaphorin 3F forms an anti-angiogenic barrier in outer retina

• The outer retina is physiologically avascular.
• Sema3F is expressed almost exclusively in photoreceptors and RPE of the outer retina.
• Sema3F inhibits sprouting angiogenesis of both retinal and choroidal endothelial cells.
• Sema3F may thus have a role in maintaining physiologic avascularity of the outer retina and may play a role in choroidal involution in late-stage AMD.

Semaphorins are known modulators of axonal sprouting and angiogenesis. In the retina, we identified a distinct and almost exclusive expression of Semaphorin 3F in the outer layers. Interestingly, these outer retinal layers are physiologically avascular. Using functional in vitro models, we report potent anti-angiogenic effects of Semaphorin 3F on both retinal and choroidal vessels. In addition, human retinal pigment epithelium isolates from patients with pathologic neovascularization of the outer retina displayed reduced Semaphorin 3F expression in 10 out of 15 patients. Combined, these results elucidate a functional role for Semaphorin 3F in the outer retina where it acts as a vasorepulsive cue to maintain physiologic avascularity.