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

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.

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Downregulation of the Netrin-1 Receptor UNC5b Underlies Increased Placental Angiogenesis in Human Gestational Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms20061408 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1408 ◽

Cited By ~ 1

Author(s):

Catalina Prieto ◽

Bárbara Casas ◽

Paulina Falcón ◽

Andrea Villanueva ◽

Pablo Lois ◽

...

Keyword(s):

Diabetes Mellitus ◽

Growth Factor ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Molecular Mechanisms ◽

Umbilical Vein ◽

Trophic Factors ◽

High Blood Glucose ◽

Glucose Levels ◽

Placental Angiogenesis

Gestational diabetes mellitus (GDM) is a common metabolic disorder, defined by high blood glucose levels during pregnancy, which affects foetal and post-natal development. However, the cellular and molecular mechanisms of this detrimental condition are still poorly understood. A dysregulation in circulating angiogenic trophic factors, due to a dysfunction of the feto-placental unit, has been proposed to underlie GDM. But even the detailed study of canonical pro-angiogenic factors like vascular endothelial growth factor (VEGF) or basic Fibroblast Growth Factor (bFGF) has not been able to fully explain this detrimental condition during pregnancy. Netrins are non-canonical angiogenic ligands produced by the stroma have shown to be important in placental angiogenesis. In order to address the potential role of Netrin signalling in GDM, we tested the effect of Netrin-1, the most investigated member of the family, produced by Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSC), on Human Umbilical Vein Endothelial Cells (HUVEC) angiogenesis. WJ-MSC and HUVEC primary cell cultures from either healthy or GDM pregnancies were exposed to physiological (5 mM) or high (25 mM) d-glucose. Our results reveal that Netrin-1 is secreted by WJ-MSC from healthy and GDM and both expression and secretion of the ligand do not change with distinct experimental glucose conditions. Noteworthy, the expression of its anti-angiogenic receptor UNC5b is reduced in GDM HUVEC compared with its expression in healthy HUVEC, accounting for an increased Netrin-1 signalling in these cells. Consistently, in healthy HUVEC, UNC5b overexpression induces cell retraction of the sprouting phenotype.

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Exogenous insulin requires MAPK activation to reverse the umbilical vein endothelial dysfunction observed in pregnant women with gestational diabetes mellitus treated with insulin

Placenta ◽

10.1016/j.placenta.2019.06.301 ◽

2019 ◽

Vol 83 ◽

pp. e95

Author(s):

Mario Subiabre ◽

Roberto Villalobos-Labra ◽

Luis Silva ◽

Gonzalo Fuentes ◽

Fernando Toledo ◽

...

Keyword(s):

Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Pregnant Women ◽

Umbilical Vein ◽

Exogenous Insulin ◽

Mapk Activation

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Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2017.11.010 ◽

2018 ◽

Vol 1864 (2) ◽

pp. 499-508 ◽

Cited By ~ 24

Author(s):

Tamara Sáez ◽

Rocío Salsoso ◽

Andrea Leiva ◽

Fernando Toledo ◽

Paul de Vos ◽

...

Keyword(s):

Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Umbilical Vein ◽

Human Umbilical Vein

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Gestational Diabetes Mellitus Treatment Schemes Modify Maternal Plasma Cholesterol Levels Dependent to Women´s Weight: Possible Impact on Feto-Placental Vascular Function

Nutrients ◽

10.3390/nu12020506 ◽

2020 ◽

Vol 12 (2) ◽

pp. 506 ◽

Cited By ~ 1

Author(s):

Susana Contreras-Duarte ◽

Lorena Carvajal ◽

María Jesús Garchitorena ◽

Mario Subiabre ◽

Bárbara Fuenzalida ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Vascular Function ◽

Plasma Cholesterol ◽

Umbilical Vein ◽

Maternal Plasma ◽

Maternal Weight ◽

Cholesterol Levels ◽

The Impact

Gestational diabetes mellitus (GDM) associates with fetal endothelial dysfunction (ED), which occurs independently of adequate glycemic control. Scarce information exists about the impact of different GDM therapeutic schemes on maternal dyslipidemia and obesity and their contribution to the development of fetal-ED. The aim of this study was to evaluate the effect of GDM-treatments on lipid levels in nonobese (N) and obese (O) pregnant women and the effect of maternal cholesterol levels in GDM-associated ED in the umbilical vein (UV). O-GDM women treated with diet showed decreased total cholesterol (TC) and low-density lipoproteins (LDL) levels with respect to N-GDM ones. Moreover, O-GDM women treated with diet in addition to insulin showed higher TC and LDL levels than N-GDM women. The maximum relaxation to calcitonin gene-related peptide of the UV rings was lower in the N-GDM group compared to the N one, and increased maternal levels of TC were associated with even lower dilation in the N-GDM group. We conclude that GDM-treatments modulate the TC and LDL levels depending on maternal weight. Additionally, increased TC levels worsen the GDM-associated ED of UV rings. This study suggests that it could be relevant to consider a specific GDM-treatment according to weight in order to prevent fetal-ED, as well as to consider the possible effects of maternal lipids during pregnancy.

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Role of Fibroblast growth factor 21 (FGF-21) as a prognostic marker for fetal and maternal complications in patients with gestational diabetes mellitus

QJM ◽

10.1093/qjmed/hcab100.126 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Mohamed Reda Halawa ◽

Magdy Hassan Kolaib ◽

Salah Hussein El-Halawany ◽

Dina Ahmed Marwan ◽

Ola Mohamed Mostafa Shaheen

Keyword(s):

Diabetes Mellitus ◽

Growth Factor ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fibroblast Growth Factor ◽

Prognostic Marker ◽

Diagnostic Marker ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth

Abstract Background Gestational diabetes mellitus (GDM) defined as glucose intolerance with onset or first diagnosis during pregnancy. While GDM usually resolves following delivery, it can have long-lasting health consequences, including increased risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD) in the mother, and future obesity, CVD, T2DM, and/or GDM in the child. This contributes to a vicious intergenerational cycle of obesity and diabetes that impacts the health of the population as a whole. Fibroblast growth factor 21 (FGF21) is a hormone that is expressed predominantly in the liver, but also in other metabolically active tissues such as pancreas, skeletal muscle and adipose tissue. An elevated FGF21 level is also an independent predictor of T2DM. GDM and T2DM are proposed to have similar underlying pathophysiologies, raising the question of whether a similar relationship exists between FGF21 and GDM as it does with T2DM. Objectives assess the role of Fibroblast growth factor 21 (FGF-21) as a prognostic marker for maternal and fetal complications in patients with gestational diabetes mellitus (GDM). Patients and Methods A case control study that was conducted on 50 patients diagnosed with Gestational Diabetes Mellitus and 50 control subjects at Diabetes and Obstetrics outpatient clinic and inpatient ward at Ain Shams university hospitals in the period between December 2018 and July 2019. Patients diagnosed with gestational diabetes mellitus (GDM) at 24-28 weeks of gestation were included in this study. Results FGF 21 levels varied significantly with blood sugar values where higher levels of FGF 21 levels were found in patients with GDM with study results showing that FGF 21 can be used as a diagnostic marker for GDM at levels above 121 pg/ml with sensitivity 84% and specificity 92%. Conclusion FGF 21 can be used as a diagnostic marker for gestational diabetes. Further studies needed for better correlation between FGF 21 levels during pregnancy and maternal outcome.

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