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

FASEB J. 2021 Jun;35(6):e21662. doi: 10.1096/fj.202002072RR.

Abstract

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.

Keywords: endothelium; gestational diabetes; mitochondria; oxidative stress; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism*
  • Cells, Cultured
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Diabetes, Gestational / physiopathology*
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Female
  • Gene Expression Regulation*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology*
  • Humans
  • In Vitro Techniques
  • Models, Biological*
  • Oxidative Stress*
  • Pregnancy
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antioxidants
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • SIRT1 protein, human
  • Sirtuin 1