Potential Role of Hyperglycemia in Fetoplacental Endothelial Dysfunction in Gestational Diabetes Mellitus

Abstract

Background: Gestational diabetes mellitus (GDM) is associated with structural and functional alterations in various tissues including endothelial dysfunction. The aim of this study was to explore the effects of hyperglycemia on fibroblast growth factor 2 (FGF2)- and vascular endothelial growth factor (VEGF)-stimulated placental angiogenesis and the underlying molecular signaling mechanisms. Methods: The density of fetal placental capillaries was examined using immunohistochemistry. Human umbilical vein endothelial cells (HUVECs) derived from GDM (dHUVECs) and normal healthy patients (nHUVECs) were used as cell models in this study. Cell proliferation, migration and tube formation were measured with an MTS assay, a transwell system and a matrigel assay, respectively. The activation of ERK1/2 was analyzed with Western blot. The specific inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) PD98059 was used to elucidate the involved signaling pathway. Results: GDM did not alter the capillary density of the fetus-placenta. Both the GDM and hyperglycemic conditions inhibited the proliferation of the FGF2- but not the VEGF-stimulated HUVECs and the basal migratory capacity. Hyperglycemic condition significantly inhibited tube formation and ex vivo angiogenesis. Moreover, hyperglycemia inhibited the FGF2- but not the VEGF-induced activation of ERK1/2. PD98059 significantly inhibited the FGF2-activated ERK1/2 phosphorylation and the FGF2-stimulated cell proliferation in HUVECs. Conclusion: Both GDM and hyperglycemia may impair placental angiogenesis by reducing HUVEC proliferation, migration and tube formation. Hyperglycemia-inhibited cell proliferation stimulated by FGF2 probably contributed to the suppression of the MEK1/2/ERK1/2 pathways in the HUVECs.

Ellagic Acid Reduces High Glucose-Induced Vascular Oxidative Stress Through ERK1/2/NOX4 Signaling Pathway

“…After this period, cells were pre-treated with 20 µM EA (Sigma Aldrich, St. Louis, MO) and then stimulated with 30 mM high glucose (HG) for 24 hours. Some set of experiments were performed in the presence of PD98059 (10mM, 30 minutes pre-incubation), a potent and selective ERK1/2 inhibitor [35]. As a control, HUVEC were maintained in 5 mM normal glucose (NG).…”

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

“…GDM is considered a prediabetic state, while it shares a series of typical pathophysiological characteristics with type 2 diabetes including insulin resistance, hyperglycemia, biochemical abnormalities, and hyperlipidemia ( Yefet et al., 2019 ). A great number of reports have revealed that the microvascular cell and vascular endothelial cell (VECs) dysfunctions occurred in the umbilical cord and placenta in GDM might lead to immediate or long-term cardiovascular disease risk ( Di Fulvio et al., 2014 ; Sultan et al., 2015 ; Zhou et al., 2016 ; Amrithraj et al., 2017 ). And endothelial dysfunction is a key cause of pathogenesis when pregnancy metabolic disorders occur, including GDM, hypertensive disorders, obesity, and hyperlipidemia ( Echeverria et al., 2020 ).…”

PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

“…It was demonstrated that EPCs could be recruited to arterial injury sites and contribute to angiogenesis [6, 7]. However, evidences show that the number of circulating EPCs is reduced and their function is impaired in patients with cardiovascular risk factors, including diabetes [8, 9]. A negative correlation between EPCs and intracellular reactive oxygen species (ROS) production has been proposed [10].…”