Decreased endostatin in db/db retinas is associated with optic disc intravitreal vascularization

Abstract

Diabetic retinopathy; Endostatin; Intravitreal vessels

Retinopatia diabètica; Endostatina; Vasos intravítres

Retinopatía diabética; Endostatina; Vasos intravítreos

Endostatin, a naturally cleaved fragment of type XVIII collagen with antiangiogenic activity, has been involved in the regulation of neovascularization during diabetic retinopathy. Here, the intracellular distribution of endostatin in healthy mouse and human neuroretinas has been analyzed. In addition, to study the effect of experimental hyperglycemia on retinal endostatin, the db/db mouse model has been used. Endostatin protein expression in mouse and human retinas was studied by immunofluorescence and Western blot, and compared with db/db mice. Eye fundus angiography, histology, and immunofluorescence were used to visualize mouse retinal and intravitreal vessels. For the first time, our results revealed the presence of endostatin in neurons of mouse and human retinas. Endostatin was mainly expressed in bipolar cells and photoreceptors, in contrast to the optic disc, where endostatin expression was undetectable. Diabetic mice showed a reduction of endostatin in their retinas associated with the appearance of intravitreal vessels at the optic disc in 50% of db/db mice. Intravitreal vessels showed GFAP positive neuroglia sheath, basement membrane thickening by collagen IV deposition, and presence of MMP-2 and MMP-9 in the vascular wall. All together, these results point that decreased retinal endostatin during experimental diabetes is associated with optic disc intravitreal vascularization. Based on their phenotype, these intravitreal vessels could be neovessels. However, it cannot be ruled out the possibility that they may also represent persistent hyaloid vessels.

This work was supported by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain (grant number PI16/00719); the Fundação para a Ciência e a Tecnologia, Ministerio da Educação e Ciência, Portugal (grant numbers SFRH/BD/95330/2013 and SFRH/BPD/102573/2014); and Fondo Europeo de Desarrollo Regional (FEDER).