Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes.

Di Tomo, Pamela; Alessio, Nicola; Falone, Stefano; Pietrangelo, Laura; Lanuti, Paola; Cordone, Valeria; Santini, Silvano Junior; Di Pietrantonio, Nadia; Marchisio, Marco; Protasi, Feliciano; Di Pietro, Natalia; Formoso, Gloria; Amicarelli, Fernanda; Galderisi, Umberto; Pandolfi, Assunta

Human umbilical cord endothelial cells (HUVECs) obtained from women affected by gestational diabetes (GD-HUVECs) display durable pro-atherogenic modifications and might be considered a valid in vitro model for studying chronic hyperglycemia effects on early endothelial senescence. Here, we demonstrated that GD- compared to C-HUVECs (controls) exhibited oxidative stress, altered both mitochondrial membrane potential and antioxidant response, significant increase of senescent cells characterized by a reduced NAD-dependent deacetylase sirtuin-1 (SIRT1) activity together with an increase in cyclin-dependent kinase inhibitor-2A (P16), cyclin-dependent kinase inhibitor-1 (P21), and tumor protein p53 (P53) acetylation. This was associated with the p300 activation, and its silencing significantly reduced the GD-HUVECs increased protein levels of P300 and Ac-P53 thus indicating a persistent endothelial senescence via SIRT1/P300/P53/P21 pathway. Overall, our data suggest that GD-HUVECs can represent an "endothelial hyperglycemic memory" model to investigate in vitro the early endothelium senescence in cells chronically exposed to hyperglycemia in vivo.