Gestational diabetes alters microRNA signatures in human feto-placental endothelial cells depending on fetal sex

2018 ◽  
Vol 132 (22) ◽  
pp. 2437-2449 ◽  
Author(s):  
Jasmin Strutz ◽  
Silvija Cvitic ◽  
Hubert Hackl ◽  
Karl Kashofer ◽  
Hannah M. Appel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gestational Diabetes ◽  
Endothelial Function ◽  
Mirna Expression ◽  
Maternal Body Mass Index ◽  
Separate Analysis ◽  
Biological Functions ◽  
Metabolic Disturbances ◽  
Fetal Sex ◽  
Male And Female

MicroRNAs (miRNAs), small non-coding RNAs, have emerged as important, epigenetic regulators of endothelial function. Metabolic disturbances such as diabetes alter miRNA expression. In adults, the miRNA transcriptome as well as endothelial function differ between the sexes. Here, we hypothesized that metabolic disturbances associated with gestational diabetes (GDM) alter miRNA signatures in feto-placental endothelial cells (fpEC), dependent on fetal sex. We isolated human primary fpEC after normal and GDM-complicated pregnancies with male and female neonates and screened for differential miRNA expression using next-generation miRNA sequencing. To test for miRNAs commonly regulated in fpEC of female and male progeny, data were stratified for fetal sex and maternal body mass index (BMI). Analyses were also performed separately for female and male fpEC, again accounting for maternal BMI as covariate. Potential biological pathways regulated by the altered set of miRNAs were determined using mirPath software. Maternal GDM altered 26 miRNA signatures when male and female fpEC were analyzed together. Separate analysis of male versus female fpEC revealed 22 GDM affected miRNAs in the females and only 4 in the males, without overlap. Biological functions potentially modulated by the affected miRNAs related to ‘Protein Processing in Endoplasmic Reticulum’ and ‘Proteoglycans in Cancer’. Maternal GDM alters miRNA signatures in fpEC, and biological functions affected by these miRNAs relate to well-known adverse functional consequences of diabetes on endothelium. GDM effects were highly dependent on fetal sex with miRNA signatures in female fpEC being more susceptible to metabolic derangements of GDM than miRNAs in male fpEC.

scholarly journals MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells

2018 ◽  
Vol 45 (5) ◽  
pp. 1878-1892 ◽  
Author(s):  
Xavier Vidal-Gómez ◽  
Daniel Pérez-Cremades ◽  
Ana Mompeón ◽  
Ana Paula Dantas ◽  
Susana Novella ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Pathway Analysis ◽  
Mirna Expression ◽  
Umbilical Vein ◽  
Mirna Gene ◽  
Mirna Profile ◽  
Human Endothelial Cells ◽  
Estrogen Regulation

Background/Aims: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERβ and GPER) in the regulation of miRNA expression by estrogen. Methods: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. Results: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERα and ERβ, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. Conclusion: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function.

scholarly journals Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

Diabetes Care ◽  
2015 ◽  
Vol 38 (5) ◽  
pp. 844-851 ◽  
Author(s):  
Ravi Retnakaran ◽  
Caroline K. Kramer ◽  
Chang Ye ◽  
Simone Kew ◽  
Anthony J. Hanley ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Fetal Sex ◽  
Maternal Risk ◽  
The Impact

scholarly journals Polarized Proteins in Endothelium and Their Contribution to Function

2021 ◽  
pp. 1-27
Author(s):  
Abigail G. Wolpe ◽  
Claire A. Ruddiman ◽  
Phillip J. Hall ◽  
Brant E. Isakson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Planar Cell Polarity ◽  
Protein Localization ◽  
Peripheral Resistance ◽  
Specific Protein ◽  
Resistance Arteries ◽  
Extracellular Stimuli ◽  
Small Resistance ◽  
Signaling Domains

Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes, abluminal membranes, and interendothelial junctions, as well as caveolae and calcium signaling domains. Protein localization in endothelial cells is also determined in part by the vascular bed, with differences between arteries and veins and between large and small arteries. Specific protein polarity and localization is essential for endothelial cells in responding to various extracellular stimuli. In this review, we examine protein localization in the endothelium of resistance arteries, with occasional references to other vessels for contrast, and how that polarization contributes to endothelial function and ultimately whole organism physiology. We highlight the protein localization on the luminal surface, discussing important physiological receptors and the glycocalyx. The protein polarization to the abluminal membrane is especially unique in small resistance arteries with the presence of the myoendothelial junction, a signaling microdomain that regulates vasodilation, feedback to smooth muscle cells, and ultimately total peripheral resistance. We also discuss the interendothelial junction, where tight junctions, adherens junctions, and gap junctions all convene and regulate endothelial function. Finally, we address planar cell polarity, or axial polarity, and how this is regulated by mechanosensory signals like blood flow.

scholarly journals Gestational diabetes induces alterations of sirtuins in fetal endothelial cells

2015 ◽  
Vol 79 (5) ◽  
pp. 788-798 ◽  
Author(s):  
Juan Gui ◽  
Arne Potthast ◽  
Anne Rohrbach ◽  
Katja Borns ◽  
Anibh M. Das ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gestational Diabetes

scholarly journals Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Solvey Pollmann ◽  
David Scharnetzki ◽  
Dominique Manikowski ◽  
Malte Lenders ◽  
Eva Brand
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Fabry Disease ◽  
Specific Inhibitor ◽  
Small Vessel ◽  
Endothelial Glycocalyx ◽  
Enzyme Replacement ◽  
Anti Inflammatory

Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p<0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p<0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p<0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p<0.01), heparin (p<0.01), anti-inflammatory (p<0.001) and antioxidant drugs (p<0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p<0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.

scholarly journals Does Maternal Body Mass Index Influence Treatment Effect in Women with Mild Gestational Diabetes?

2014 ◽  
Vol 32 (01) ◽  
pp. 093-100
Author(s):  
Lisa Mele ◽  
Mark Landon ◽  
Catherine Spong ◽  
Susan Ramin ◽  
Ronald Wapner ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Gestational Diabetes ◽  
Body Mass ◽  
Treatment Effect ◽  
Maternal Body Mass Index ◽  
Maternal Body

scholarly journals Sirtuin1 protects endothelial Caveolin-1 expression and preserves endothelial function via suppressing miR-204 and endoplasmic reticulum stress

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Modar Kassan ◽  
Ajit Vikram ◽  
Young-Rae Kim ◽  
Qiuxia Li ◽  
Adam Kassan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Endothelial Function ◽  
Er Stress ◽  
High Fat Diet ◽  
Important Determinant ◽  
Class Iii ◽  
Caveolin 1 ◽  
Physiological Processes

Abstract Sirtuin1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including endothelial function. Caveolin1 (Cav1) is also an important determinant of endothelial function. We asked if Sirt1 governs endothelial Cav1 and endothelial function by regulating miR-204 expression and endoplasmic reticulum (ER) stress. Knockdown of Sirt1 in endothelial cells, and in vivo deletion of endothelial Sirt1, induced endothelial ER stress and miR-204 expression, reduced Cav1, and impaired endothelium-dependent vasorelaxation. All of these effects were reversed by a miR-204 inhibitor (miR-204 I) or with overexpression of Cav1. A miR-204 mimic (miR-204 M) decreased Cav1 in endothelial cells. In addition, high-fat diet (HFD) feeding induced vascular miR-204 and reduced endothelial Cav1. MiR-204-I protected against HFD-induced downregulation of endothelial Cav1. Moreover, pharmacologic induction of ER stress with tunicamycin downregulated endothelial Cav1 and impaired endothelium-dependent vasorelaxation that was rescued by overexpressing Cav1. In conclusion, Sirt1 preserves Cav1-dependent endothelial function by mitigating miR-204-mediated vascular ER stress.

Perinatal Maternal and Neonatal Outcomes in Women With Gestational Diabetes Mellitus According to Fetal Sex

2012 ◽  
Vol 9 (6) ◽  
pp. 411-417 ◽  
Author(s):  
Diana Tundidor ◽  
Apolonia García-Patterson ◽  
Miguel A. María ◽  
Justa Ubeda ◽  
Gemma Ginovart ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Neonatal Outcomes ◽  
Fetal Sex ◽  
Maternal And Neonatal Outcomes

Differential effects of obesity on visceral vs. subcutaneous adipose arteries: role of shear activated Kir2.1 and alterations to the glycocalyx

2021 ◽  
Author(s):  
Sang Joon Ahn ◽  
Elizabeth Le Master ◽  
James C. Lee ◽  
Shane A. Phillips ◽  
Irena Levitan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Dominant Negative ◽  
Obese Mice ◽  
Shear Sensitivity ◽  
Electrophysiological Recordings ◽  
Subcutaneous Adipose

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow-sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAA), but not subcutaneous adipose arteries (SAA), exhibit endothelial dysfunction. Aim: To determine if differences in SAA vs. VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx. Methods: Mice were fed a normal rodent diet, or a high fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Results: Endothelial dysfunction was observed in VAA of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAA, but had no effect on VAA, from obese mice and humans. Obesity abolished Kir shear-sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear-sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. Conclusions: We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA vs. VAA endothelial function with obesity.

Sign in / Sign up

Export Citation Format

Share Document