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N. Sagara, M. Inatani, T. Kawaji, Y. Inomata, H. Tanihara; Effect of Heparin on Experimental Retinal Neovascularization in Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3400.
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Vascular endothelial growth factor (VEGF) plays a primary role in both pathological and physiological angiogenesis. The cell surface of vascular endothelium expresses heparan sulfate (HS) / heparan sulfate proteoglycans, which demonstrate affinity for VEGF. In the present study, we investigated the interaction between HS / heparin and VEGF in experimental retinal neovascularization.
To examine heparin/HS-binding properties of VEGF, binding assay was performed using biotinylated HS and recombinant mouse VEGF164 or VEGF120. C57BL/6 mice at postnatal day (P) 7 were exposed to 75% oxygen (O2) for 5 days and allowed to recover in room air to induce retinal neovascularization. Animals had been treated with the intraperitoneal injection of heparin or vehicle once daily since P12. FITC-dextran perfusion method was performed at P17 and P21 to evaluate the avascular area. The retinal neovascularization was quantified histologically by counting the nuclei of new vessels extending from the retina into the vitreous at P17 and P21. The concentrations of VEGF in the retina at P13, P17 and P21 were evaluated with ELISA.
Binding assay demonstrated that VEGF164 bound to HS in a dose-dependent manner while VEGF120 did not bind to HS. In mice experimental model, retinal avascular area in heparin-treated pups significantly expanded at P21, compared with the area in vehicle-treated pups. Moreover, at P17, the number of nuclei of new vessels in heparin-treated pups was significantly fewer than the number in vehicle-treated pups. In contrast, there was no significant difference in retinal VEGF concentration at P17 between heparin-treated pups and vehicle-treated pups.
The present findings suggest that retinal angiogenesis can be disturbed by exogenous heparin / HS. HS may be a regulating factor for VEGF-induced angiogenesis in vivo.
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