2. Academic Validation
  3. Impaired angiogenesis in gestational diabetes is linked to succinate/SUCNR1 axis dysregulation in late gestation

Impaired angiogenesis in gestational diabetes is linked to succinate/SUCNR1 axis dysregulation in late gestation

  • J Physiol. 2025 Mar 31. doi: 10.1113/JP288010.
Sergiy Klid 1 2,  Francisco Algaba-Chueca 2 3,  Elsa Maymó-Masip 2 3,  Mónica Ballesteros 1 2 4,  Montse Inglés 1 2 4,  Albert Guarque 1 2 4,  Nerea Vilanova-Ricart 1 3,  Ariadna Prats 3,  Azra Kulovic-Sissawo 5,  Elisa Weiss 5,  Ursula Hiden 5,  Joan Vendrell 1 2 3,  Sonia Fernández-Veledo 1 2 3,  Ana Megía 1 2 3
Affiliations

Affiliations

  • 1 Department of Medicine and Surgery, Rovira i Virgili University, Tarragona, Spain.
  • 2 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
  • 3 Department of Endocrinology and Nutrition, Research Unit, University Hospital of Tarragona Joan XXIII-Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain.
  • 4 Department of Obstetrics and Gynecology, University Hospital of Tarragona Joan XXIII. Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain.
  • 5 Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
PMID: 40163642 DOI: 10.1113/JP288010
Abstract

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.

Keywords

HUVEC; SUCNR1; angiogenesis; gestational diabetes mellitus; pregnancy; succinate.

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