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Guorui Dou, Yusheng Wang, Hua Han, Xingcheng Zhao; Pleiotropic effects of Dll1-RGD in mice oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5555.
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Recent progress highlights Notch signaling in ischemia-related ocular angiogenesis. Delta like 1(Dll1), a critical Notch ligand in vascular development, has been identified as a potential facilitator of reparative angiogenesis. Here, we construct a novel fusion protein Dll1-RGD containing RGD motif that can ligate endothelial cell (EC) integrin, to investigate its role on mice models of oxygen induced retinopathy by specific activation of Notch in EC.
Dll1-RGD fusion was manufactured in E.Coli. The specification of this recombinant to EC was observed by adherence assay. Its Notch activating activity was detected in human umbilical vein endothelial cells (HUVEC) and confirmed by the downstream genes. The role of Dll1-RGD on vascular growth was observed in neonatal C57BL/6J mice injected with Dll1-RGD subcutaneously. Bead assay, transwell chamber and tube formation were conducted to study biological behaviors of HUVEC treated by Dll1-RGD. Neonatal C57BL/6J mice was taken into 75% oxygen chamber from P7-P12 and were injected with Dll1-RGD subcutaneously on P12. The area of retinal angiogenesis was analyzed on P17.
Dll1-RGD could specifically adhere to the endothelial cells. Dll1-RGD greatly enhanced Notch signaling and upregulated the Notch downstream genes in EC. In vitro, the anti-angiogenic role of Dll1-RGD was identified in the endothelial cell sprouting, migration and tube formation. In the developing retinal vascular formation, Dll1-RGD attenuated the growth of retinal vasculature, as branching loops and tip cells were greatly decreased. Specific activation of Notch by Dll1-RGD induced regrowth of retinal vessels following oxygen-induced retinopathy on P17. Pleiotropically, it prevented the formation of preretinal neovascular tufts, but promotes formation of intraretinal capillaries following oxygen-induced retinopathy.
Our data provide Dll1-RGD as a potential therapeutic strategy to ischemia-related ocular angiogenesis by enhancing Notch signaling in EC.
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