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Rob J. Van Geest, Ingeborg Klaassen, Ilse M. C. Vogels, Cornelis J. F. Van Noorden, Reinier O. Schlingemann; Differential TGF-β Signaling in Retinal Vascular Cells: A Role in Diabetic Retinopathy?. Invest. Ophthalmol. Vis. Sci. 2010;51(4):1857-1865. doi: 10.1167/iovs.09-4181.
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© ARVO (1962-2015); The Authors (2016-present)
An early hallmark of preclinical diabetic retinopathy is thickening of the capillary basal lamina (BL). TGF-β, a multipotent cytokine acting through its receptors ALK5 and -1, has been postulated to be involved in this phenomenon. In light of this possible role, TGF-β signaling and its downstream molecular effects were characterized in cultured vascular endothelial cells and pericytes of the retina.
Bovine retinal endothelial cells and pericytes were stimulated with TGF-β1 in the presence or absence of SD-208, a specific inhibitor of the TGF-β type I receptor ALK5, or ALK5 small interfering (si)RNA. TGF-β-signaling pathways were characterized by analysis of phosphorylated Smad2 or -1/5/8 proteins and TGF-β target genes (PAI-1, fibronectin, CTGF, Smad7, and Id1) and protein (fibronectin).
ALK5 was expressed in both cell types, whereas ALK1 was exclusively expressed in endothelial cells. In endothelial cells, TGF-β induced Smad2 phosphorylation at high concentrations, which was efficiently blocked by ALK5 inhibition. In contrast, in pericytes, Smad2 phosphorylation was rapidly induced at low concentrations of TGF-β. The ALK1-Smad1/5/8 pathway was activated by TGF-β in endothelial cells only. TGF-β caused ALK5-mediated upregulation of PAI-1, Smad7, and fibronectin and in pericytes at lower TGF-β concentrations than in endothelial cells. CTGF mRNA expression was induced only in pericytes. Fibronectin protein was confirmed to be regulated by TGF-β in both cell types.
TGF-β signaling in retinal endothelial cells and pericytes show that these cells, and in particular the pericytes, have the essential characteristics to allow for a role of TGF-β in BL thickening in preclinical diabetic retinopathy.
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