Gestational diabetes mellitus and fetoplacental vasculature alterations: Exploring the role of adenosine kinase in endothelial (dys)function

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    Gestational diabetes mellitus (GDM) is a pregnancy disease characterized by maternal high blood glucose in the second or third trimester. GDM increases the cardiovascular risk in the offspring. GDM fetoplacental vasculature is characterized by endothelial dysfunction, proinflammation and increased angiogenesis. Adenosine regulates vascular function. In the fetoplacental circulation during GDM, an accumulation of adenosine is reported. In this thesis, we explored the role of adenosine kinase (AK), the main regulator of adenosine, in fetoplacental endothelial dysfunction during GDM. We used human umbilical vein endothelial cells (HUVECs), incubated with basal (BG) or high D-glucose (HG) (to mimic normal and high blood glucose) and/or tumor necrosis factor alpha (TNF⍺) (proinflammatory stimulus). To assess the role of AK we used ABT-702, an AK inhibitor. We evaluated mRNA and protein expression of adenosine regulators, enzymes involved in cellular methylation reactions, markers of endothelial dysfunction, inflammation, angiogenesis, and mitochondrial parameters. In HUVECs, we found that HG altered adenosine regulators, methylation, endothelial dysfunction and proinflammatory markers. HG did not alter the expression of angiogenesis markers nor cell migration. AK inhibition reduced the proinflammatory effect of HG. Moreover, ABT-702 increased cell migration only under BG. The proinflammatory effect of TNF⍺ was reduced by AK inhibition. HG and TNF⍺ had an effect on different parameters in the mitochondria in which AK seems not to play a role. Our data in HUVECs, show that HG and TNF⍺ can partly mimic the effects observed on GDM fetoplacental vasculature, and AK might play a role in some of those effects.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • Faas, Marijke, Supervisor
    • Plosch, Torsten, Supervisor
    • de Vos, Paul, Supervisor
    • Sobrevia, Luis, Supervisor, Externe Persoon
    Datum van toekenning19-feb-2020
    Plaats van publicatie[Groningen]
    Uitgever
    Gedrukte ISBN's9789464020472
    DOI's
    StatusPublished - 2020

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