The role of the TGF-ß superfamily of growth factors in diabetic retinopathy

Diabetic retinopathy (DR) causes blindness by intra-ocular angiogenesis and scarring. DR is preceded by pre-clinical DR,  a phase characterized by intra-retinal basement membrane thickening and pericyte and endothelial apoptosis and proliferation. Although its pathogenesis is incompletely understood, both in pre-clinical DR and proliferative DR, growth factors (GFs) are causally involved.

The TGF-β superfamily of GFs, which includes TGF-βs and bone morphogenetic proteins (BMPs) has important cell- and context-dependent functions in the regulation of extracellular matrix turnover, fibrosis and angiogenesis, but evidence for involvement of these GFs in DR is inconclusive. Recently, the signalling pathways of these GFs were defined, and specifically in endothelial cells, two distinct pathways were discovered that allow pro- or anti-angiogenic signalling by TGF-β through its receptors ALK1 and ALK5. In other cell types, the balance between TGF-β and BMP signalling regulates fibrosis.

In the light of these recent discoveries, we hypothesize that the TGF-β superfamily of GFs is intricately involved in the pathogenesis of DR. Therefore, the present project aims to define the possible role of 1) a disturbed TGF-β/BMP signalling balance in retinal cells in basement membrane thickening and other features of pre-clinical DR, 2) the role of increased or decreased ALK1/endoglin mediated signalling by TGF-βs in intra-retinal endothelial cells in pre-clinical DR, and 3) the role of changes in the TGF-β/BMP balance in the vitreous in angiogenesis and subsequent fibrosis in proliferative DR.

To this end, we will investigate which TGF-β superfamily GFs and their signalling molecules are expressed in the retina in humans and rodents, and how expression changes in the course of development of DR. In (transgenic) mouse models with streptozotocin-induced diabetes, we will investigate by conditional deletion of TGF-β signalling pathways whether these are necessary for the development of pre-clinical DR. By retinal transfection with constitutively active TGF-β receptors we will attempt to define whether activity of certain TGF-β signalling pathways is sufficient to cause DR-like changes in the retina. In addition, we will investigate in ocular samples of human DR how levels of TGF-β GFs are related to angiogenesis and fibrosis in proliferative DR.

This project is funded by The Dutch Diabetes Foundation