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Ashley Michael Mackey, Jorge Aranda, Chiara Gerhardinger, Andrius Kazlauskas; Development and Characterization of a new Mouse Model of Proliferative Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4676.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is a leading cause of blindness in the US adult working population. Long term diabetes mellitus (DM) results in damage to the retina and loss of retinal vessels. This ultimately leads to ischemia/hypoxia of the neural retina and vision loss. This hypoxic environment of the retina triggers an angiogenic response whereby surviving vessels begin to proliferate and form new leaky capillaries that often protrude into the vitreous body, thus establishing proliferative diabetic retinopathy (PDR). Although current therapies are effective in preventing vision loss, they have damaging side effects and are not effective in all patients. Thus there is a need to develop new therapies and drugs to both prevent neovascularization in DR, and to treat it once it has occurred. One of the obstacles to achieving this goal is the paucity of rodent models of PDR. The purpose of this study was to develop a rodent model that displays not only the early stages of DR, but also the angiogenic phase in which new, abnormal blood vessels break through the inner limiting membrane and expand into the vitreous as they do in human PDR patients.
We generated a new PDR rodent model by inducing diabetes in PHD+/- mice that display a hypoxic phenotype. DM was induced by Streptozotocin administration. Fluorescein angiography, optical coherence tomography, morphometric analysis, orthogonal confocal microscopy of retinal flatmounts and retinal sectioning were used to study the retinal vasculature and neovascularization associated with the progression of PDR in our rodent model.
Human-like PDR characteristics were visualized in our 9 month diabetic PDR rodent model. Isolectin B4 staining of retinal flatmounts from our diabetic PDR mice displayed tortuous and disorganized retinal vessels when compared to non-diabetic control mice. FA also revealed tortuous blood vessels that progressively worsened with the duration of diabetes. Finally, we observed retinal tufts (pre-retinal neovascularization) above the inner limiting membrane only in retinal sections from diabetic mice.
We have successfully developed a rodent model that recapitulates the pathology of human PDR. This may serve as a relevant model for investigation of the angiogenic phase of PDR and the identification of molecular pathways for therapeutic intervention in human disease.
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