P76Notch signaling up-regulation in diabetic epicardial adipose-tissue stem cells and angiogenic function

Purpose: Type 2 diabetes mellitus patients have an increased risk of developing atherosclerosis and coronary heart disease. The epicardial adipose tissue is a reservoir of adipose-tissue mesenchymal stem cells (EAT-ASCs), with yet unknown effects on myocardial and coronary arteries homeostasis. The aim of this study has been to elucidate the regulation of EAT-ASCs function in diabetes. Methods: EAT-ASCs were obtained from Zucker Diabetic Fatty (ZDF) and non-diabetic lean control (ZLC) rats. EAT-ASCs function was assessed by proliferation assays, flow cytometry, in vitro differentiation and gene expression analysis. Results: EAT-ASCs from ZDF rats showed up-regulation of downstream Notch signaling genes Hes7 (1.6-fold; p=0.0017), Hey1 (1.8-fold; p=0.0346) and HeyL (1.8-fold; p=0.0325) and lower proliferation rates than EAT-ASCs from ZLC rats (p=0.0211). Both types of EAT-ASCs showed similar adipogenic and osteogenic differentiation capacity. However, ZDF-EAT-ASCs had lower differentiation to endothelial cells as well as a reduced ability to form angiotubes compared to ZLC-EAT-ASCs (-13.9-fold angiotube length; p=0.0393). Notch signaling inhibition by a gamma-secretase inhibitor (DAPT) induced a reduction in Hes/Hey gene expression and rescued angiotube formation function in ZDF-EAT-ASCs. These results indicate that over-activation of Notch signaling pathway reduces the angiogenic function in epicardial ASCs. Conclusion: Diabetes mellitus impairs EAT-ASCs angiogenic potential by an up-regulation of Notch downstream signaling.