Inhibition of pathological retinal neovascularization by semaphorin 3A.

Wenzhen Yu, Yujing Bai, Na Han, Fei Wang, Min Zhao, Lvzhen Huang, Xiaoxin Li

Molecular vision 2013

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Pathological retinal angiogenesis is a major cause of vision loss. Semaphorin 3A (Sema3A), a chemorepellent guidance protein, plays crucial roles in neural and vascular patterning. To identify its role in retinal neovascularization, we investigated its antiangiogenic effects. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study, and an oxygen-induced retinopathy (OIR) mouse model was used for the in vivo study. The HUVECs were incubated with Sema3A, and cell proliferation, migration, apoptosis, cell cycle, tube formation, and c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (p38 MAPK) signaling pathways were measured using Cell Counting Kit-8, Transwell, flow cytometry, Matrigel assays, and western blot. C57BL/6J mouse pups were exposed to 75% oxygen for 5 days and then brought to room air and injected with Sema3A intravitreously. At postnatal day 18, the retinal nonperfused areas were measured. The in vitro and in vivo vascular endothelial growth factor-165 (VEGF165) secretion was measured using enzyme-linked immunosorbent assay. Sema3A not only inhibited VEGF165-induced proliferation, but also induced cell cycle arrest in a dose-dependent manner. Furthermore, Sema3A inhibited migration and tube formation, both in general and in VEGF165-containing culture medium. Using an enzyme-linked immunosorbent assay, we showed that Sema3A did not affect VEGF165 secretion, but it did impede VEGF165 function. Additionally, Sema3A significantly inhibited the phosphorylation of the JNK and p38MAPK signaling pathways. When administered intravitreously, Sema3A reduced the pathological vascular changes seen in the retinal neovascularization OIR model. These results suggest that the administration of Sema3A could be a useful therapeutic strategy for preventing hypoxia/ischemic-induced retinal neovascularization.

Citation

Wenzhen Yu, Yujing Bai, Na Han, Fei Wang, Min Zhao, Lvzhen Huang, Xiaoxin Li. Inhibition of pathological retinal neovascularization by semaphorin 3A. Molecular vision. 2013;19:1397-405