Endothelial-to-mesenchymal transition: An underappreciated mediator of diabetic complications

Figures

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  Figure 1. Endothelial to mesenchymal transition. ECs can undergo EndMT in response to a variety of stimuli. EndMT is characterized by reduced expression of endothelial markers (green) and increased expression of mesenchymal markers (red). Common inducers of EndMT include NOTCH, WNT, TGF-β, ET-1, and inflammatory signaling. TGF-β is the best characterized and most common driver of EndMT. Canonical TGF-β signaling through SMAD2/3, non-canonical TGF-β signaling through other mechanisms such as MAPK, PI3K and PKC-δ, as well as other EndMT inducers such as NOTCH, WNT, and ET-1 generally converge through the regulation of key transcription factors such as SNAI and Twist in order to reduce endothelial protein expression and promote mesenchymal protein expression. Inflammatory cytokines contribute to EndMT by activating NF-κB. Cells undergoing EndMT co-express endothelial and mesenchymal markers.

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  Figure 2. Epigenetic regulation of endothelial to mesenchymal transition. Induction and maintenance of EndMT is facilitated by changes in epigenetic regulation. Stimuli such as TGF-β, NOTCH, WNT, ET-1, inflammatory cytokines, which may result from hyperglycemia can effect changes in epigenetic regulation, resulting in persistently altered patterns of gene expression. Different epigenetic mechanisms also reciprocally regulate one another. DNA methylation, and histone modifications can influence the transcription of ncRNAs, while ncRNAs can regulate the proteins required for covalent modifications of DNA and histones. Different types of ncRNAs regulate also each other, with circRNAs and lncRNAs sponging miRNAs while miRNAs can target circRNAs and lncRNAs for degradation.