Deletion of Ocular Transforming Growth Factor β Signaling Mimics Essential Characteristics of Diabetic Retinopathy

Abstract

Diabetic retinopathy, a major cause of blindness, is characterized by a distinct phenotype. The molecular causes of the phenotype are not sufficiently clear. Here, we report that deletion of transforming growth factor β signaling in the retinal microenvironment of newborn mice induces changes that largely mimic the phenotype of nonproliferative and proliferative diabetic retinopathy in humans. Lack of transforming growth factor β signaling leads to the formation of abundant microaneurysms, leaky capillaries, and retinal hemorrhages. Retinal capillaries are not covered by differentiated pericytes, but by a coat of vascular smooth muscle-like cells and a thickened basal lamina. Reactive microglia is found in close association with retinal capillaries. In older animals, loss of endothelial cells and the formation of ghost vessels are observed, findings that correlate with the induction of angiogenic molecules and the accumulation of retinal hypoxia-inducible factor 1α, indicating hypoxia. Consequently, retinal and vitreal neovascularization occurs, a scenario that leads to retinal detachment, vitreal hemorrhages, neuronal apoptosis, and impairment of sensory function. We conclude that transforming growth factor β signaling is required for the differentiation of retinal pericytes during vascular development of the retina. Lack of differentiated pericytes initiates a scenario of structural and functional changes in the retina that mimics those of diabetic retinopathy strongly indicating a common mechanism.

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

“…A comparable lack of vessel formation in the retina has been observed in another transgenic mouse strain with high amounts of ocular TGF-β1 (Zhao and Overbeek 2001a). We recently reported that mice with conditional ocular deletion of TGF-β signaling during the development of the retinal vasculature in the first weeks of postnatal life show a massive proliferation of retinal capillaries that results in a pronounced preretinal neovascularization (Braunger et al 2015). Consequently, high activity of retinal TGF-β1 might well induce antiproliferative effects on retinal vascular endothelial cells.…”

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…In transgenic Tgfbr2 Δeye mice, deletions in elements of the TGF-β pathway have been shown to determine the impairment of pericyte differentiation, which resulted in structural and functional changes in the retina that mimic those of diabetic retinopathy [53].…”

The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels

“…Indeed, the vascular phenotype resulting from conditional deletion of the Tgf-b type II receptor in the eyes of newborn mice shows most of the characteristic features of diabetic retinopathy. 29 The biosynthetic changes that we observed in the retinal vessels of the diabetic rats treated with SM16 provide molecular mechanisms for the above abnormalities. In our study, SM16 treatment undermined in retinal vessels at least three stabilizing influences: i) the angiopoietin 1/TEK receptor tyrosine kinase paracrine loop 26 ; ii) integrins a 5 and a V , the combined absence of which causes extensive defects in vessel stability and remodeling 30 ; and iii) collagen-18, which has a structural role in maintaining basement membrane integrity.…”

“…27 However, when SM16 was given to diabetic rats and deprived the retinal vessels of the small increment in Tgf-b signaling induced by diabetes, the vessels showed an image of profound distress, similar to that observed in normal murine vessels after sustained inhibition of constitutive Tgf-b signaling by receptor deletion or receptor antagonists. Whether tested in embryonic, 28 newborn, 29 or adult 9 mice, these interventions have caused vessels to become leaky and unstable, often totally or partially collapsed, and nonperfused. Indeed, the vascular phenotype resulting from conditional deletion of the Tgf-b type II receptor in the eyes of newborn mice shows most of the characteristic features of diabetic retinopathy.…”