Inhibition of Notch rescues the angiogenic potential impaired by cardiovascular risk factors in epicardial adipose stem cells

• Published in: The FASEB journal 2016-08, Vol.30 (8), p.2849-2859
• Main Authors: Bejar, Maria Teresa, Ferrer‐Lorente, Raquel, Peña, Esther, Badimon, Lina
• Format: Article
• Language: English
• Subjects: Adipose Tissue - cytology; angiogenesis; Animals; Cardiovascular Diseases - etiology; Diabetes Mellitus; differentiation; epicardial adipose tissue; Gene Expression Regulation - physiology; Hes/Hey family; Male; Myocytes, Cardiac - metabolism; Neovascularization, Pathologic - metabolism; Obesity; Rats; Rats, Zucker; Receptors, Notch - genetics; Receptors, Notch - metabolism; Risk Factors; Stem Cells - physiology; Up-Regulation; ZDF
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201600204R

ABSTRACT The epicardial adipose tissue (EAT) is a reservoir of adipose‐derived stem cells (ASCs), with as yet unknown effects on myocardial and coronary arteries homeostasis. The purpose of this study was to investigate the angiogenic function of epicardial ASCs and their regulation by the common cardiovascular risk factors (CVRFs) affecting heart disease. Epicardial fat was obtained from a rodent model with clustering of CVRFs [Zucker diabetic fatty (ZDF)‐Leprfa] rats and from their lean control (ZDF‐Crl) littermates without CVRFs, ASCs were isolated, and their function was assessed by proliferation and differentiation assays, flow cytometry, gene expression, and in vivo Matrigel angiogenesis analysis. Epicardial ASCs from both groups showed adipogenic and osteogenic differentiation capacity; however, epicardial ASCs from CVRF animals had a lesser ability to form tubular structures in vitro after endothelial differentiation, as well as a reduced angiogenic potential in vivo compared to control animals. Epicardial ASCs from CVRF rats showed up‐regulation of the downstream Notch signaling genes Hes7, Hey1, and Heyl compared with control animals. The inhibition of Notch signaling by conditioning epicardial ASCs from CVRF animals with a γ‐secretase inhibitor induced a reduction in Hes/Hey gene expression and rescued their angiogenic function in vivo. We report for the first time the impact of CVRF burden on the ASCs of EAT and that the defective function is in part caused by increased Notch signaling. Conditioning ASCs by blocking Notch signaling rescues their angiogenic potential.—Bejar, M. T., Ferrer‐Lorente, R., Peña, E., Badimon, L. Inhibition of Notch rescues the angiogenic potential impaired by cardiovascular risk factors in epicardial adipose stem cells. FASEB J. 30, 2849‐2859 (2016). www.fasebj.org