Klid Sergiy, Algaba-Chueca Francisco, Maymó-Masip Elsa, Ballesteros Mónica, Inglés Montse, Guarque Albert, Vilanova-Ricart Nerea, Prats Ariadna, Kulovic-Sissawo Azra, Weiss Elisa, Hiden Ursula, Vendrell Joan, Fernández-Veledo Sonia, Megía Ana
Department of Medicine and Surgery, Rovira i Virgili University, Tarragona, Spain.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
J Physiol. 2025 Mar 31. doi: 10.1113/JP288010.
Recent research has highlighted the significance of succinate and its receptor in gestational diabetes (GDM) pathogenesis. However, a clear interconnection between placenta metabolism, succinate levels, SUCNR1 signalling and pregnancy pathologies remains elusive. Here, we set out to investigate the potential role of succinate on labour and placental mechanisms by combining clinical and functional experimental data at the same time as exploring the specific SUCNR1-mediated effects of succinate on placenta vascularization, addressing its specific agonist actions. According to our data, succinate levels vary throughout pregnancy and postpartum, with a natural increase during the peripartum period. We also show that SUCNR1 activation in the umbilical cord endothelium promotes angiogenesis under normal conditions. However, in GDM, excessive succinate and impaired SUCNR1 function may weaken this angiogenic response. In conclusion, the present study underlines succinate as an emerging signalling molecule in the placenta, regulating labour and placental processes. The reduced sensitivity of the succinate/SUCNR1 pathway in the GDM environment may serve as a protective physiological mechanism or could have a pathogenic effect. KEY POINTS: Succinate levels increase at delivery in maternal and fetal circulation. Gestational diabetes (GDM) induces succinate accumulation and SUCNR1 downregulation in umbilical cords. GDM compromises angiogenic gene profile modulation by SUCNR1 in umbilical cord endothelium. SUCNR1 activation stimulates sprouting and tube-forming capacity of human umbilical vein endothelial cells from healthy, but not GDM pregnancies.
近期研究突显了琥珀酸及其受体在妊娠期糖尿病（GDM）发病机制中的重要性。然而，胎盘代谢、琥珀酸水平、SUCNR1信号传导与妊娠病理之间的明确联系仍不清晰。在此，我们通过整合临床和功能实验数据，同时探索琥珀酸对分娩和胎盘机制的潜在作用，以及琥珀酸通过SUCNR1介导对胎盘血管生成的特定影响，来研究其具体的激动剂作用。根据我们的数据，琥珀酸水平在整个孕期和产后有所变化，在围产期自然升高。我们还表明，在正常条件下，脐带内皮细胞中的SUCNR1激活可促进血管生成。然而，在GDM中，过量的琥珀酸和受损的SUCNR1功能可能会削弱这种血管生成反应。总之，本研究强调琥珀酸是胎盘中一种新兴的信号分子，可调节分娩和胎盘过程。在GDM环境中，琥珀酸/SUCNR1途径敏感性降低可能是一种保护性生理机制，也可能具有致病作用。要点：母体和胎儿循环中琥珀酸水平在分娩时升高。妊娠期糖尿病（GDM）导致脐带中琥珀酸积累和SUCNR1下调。GDM损害SUCNR1对脐带内皮细胞血管生成基因谱的调节。SUCNR1激活刺激健康妊娠而非GDM妊娠的人脐静脉内皮细胞的芽生和管形成能力。
