The RhoA guanine exchange factor ABR: a glucose-sensitive mediator of actin reorganization in feto-placental arterial endothelial cells altered by gestational diabetes mellitus.

Autor: Tokic S; Department of Paediatrics and Adolescent Medicine, Research Unit of Analytical Mass Spectrometry, Cell Biology and Biochemistry of Inborn Errors of Metabolism, Medical University of Graz, Graz, Austria., Novakovic B; Complex Disease Epigenetics, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia., Leopold-Posch B; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria., Mühlberger M; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria., Hoch D; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria., Lögl J; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria., Bernhart EM; Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria., Saffery R; Complex Disease Epigenetics, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia., Desoye G; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria., Hiden U; Department of Obstetrics and Gynecology, Research Unit of Early Life Determinants (ELiD), Medical University of Graz, Graz, Austria.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2024 May 22. Date of Electronic Publication: 2024 May 22.
DOI: 10.1113/JP285910
Abstrakt: In utero exposure to gestational diabetes mellitus (GDM) programs the fetus, increasing offspring risk for endothelial dysfunction and cardiovascular disease later in life. Hyperglycaemia is widely recognized as the driving force of diabetes-induced programming. We have previously shown that GDM exposure alters DNA methylation and gene expression associated with actin remodelling in primary feto-placental arterial endothelial cells (fpEC). Thus, we hypothesized that hyperglycaemic insults underlie programmed changes in fpEC morphology and actin organization by GDM. Therefore, arterial fpECs isolated after normal and GDM pregnancy, as well as normal fpECs that were exposed to hyperglycaemia in vitro, were analysed for the effect of GDM and hyperglycaemia on actin organization and network formation. Integration of gene expression and DNA methylation data identified the RhoA activator active BCR-related (ABR) as programmed by GDM and altered by in vitro hyperglycaemia. ABR silencing in GDM-exposed cells reduced RhoA activity by 34 ± 26% (P = 0.033) and restored normal fpEC phenotype. In fact, in vitro hyperglycaemia induced a similar fpEC phenotype as intrauterine exposure to GDM, i.e. round morphology and increased network formation on Matrigel by 34 ± 33% (P = 0.022) vs. 22 ± 20% for GDM (P = 0.004). Thus, we identified ABR as a novel glucose sensitive regulator of actin organization and cell shape, programmed by GDM and upregulated by hyperglycaemia. Identification of mechanisms induced by hyperglycaemia and affecting endothelial function in the long term will contribute to understanding GDM-induced programming of offspring endothelial dysfunction and cardiovascular disease. Future studies could focus on investigating the prevention or reversal of such malprogramming. KEY POINTS: In utero exposure to gestational diabetes mellitus (GDM) affects future health of the offspring, with an increased risk for endothelial dysfunction and cardiovascular disease in later life. GDM alters DNA methylation and expression of ABR in feto-placental arterial endothelial cells (fpEC), a model for endothelial cells exposed to the intrauterine environment of the fetus. GDM phenotype of fpECs is also induced by hyperglycaemia in vitro, and is characterized by altered actin organization and cell shape, which can be restored by ABR silencing. Revealing the cellular mechanisms induced by GDM and hyperglycaemia is important for understanding the mechanisms of how these conditions disturb endothelial function in the offspring.
(© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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