gms | German Medical Science

Background: Proliferative retinopathies such as retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are leading causes for acquired blindness in children and middle aged patients. Beyond the age of 65, age related macular degeneration (AMD) represents a major cause for severe vision loss. In all three entities, the angiorepulsive effect of semaphorins may have important angiomodulatory functions.

Methods: Semaphorin expression was analyzed in murine retina during normal development as well as oxygen-induced retinopathy (OIR) using laser-capture microdissection and qPCR. Results were confirmed using Western Blot and immunohistochemistry. Functional experiments were carried out using an in vitro model of endothelial sprouting angiogenesis as well as lentiviral, shRNA-mediated knockdown of semaphorins in the OIR mouse model.

Results: Semaphorins were found to display differential expression patterns in murine retina. Sema3A is primarily expressed in retinal ganglion cells and is significantly upregulated during retinal hypoxia. In vitro, semaphorins potently inhibit endothelial sprouting angiogenesis. Lentiviral knockdown of angiorepulsive Sema3A in the OIR model significantly improves retinal revascularization of avascular retinal areas, thus reducing the severity of subsequent proliferative retinopathy.

Conclusion: Semaphorins appear to have important angiomodulatory roles in neovascular eye disease. During proliferative retinopathy, Sema3A exerts angiorepulsive effects that prevent an efficient revascularization of avascular retina. Modulation of semaphorins may thus potentially be used to improve revascularization of avascular retina, an approach upstream of current anti-VEGF therapies which target the subsequent proliferative changes.