Impaired angiogenesis in gestational diabetes is linked to succinate/SUCNR1 axis dysregulation in late gestation.
Summary
Combining clinical sampling with endothelial functional assays, the study shows that succinate rises around delivery, and SUCNR1 activation promotes angiogenesis in umbilical endothelium under normal conditions. In gestational diabetes, succinate accumulation with SUCNR1 downregulation blunts SUCNR1-driven angiogenic gene programs and sprouting/tube formation, implicating succinate/SUCNR1 dysregulation in impaired placental vascularization.
Key Findings
- Succinate levels naturally increase during the peripartum in maternal and fetal circulation.
- GDM umbilical cords show succinate accumulation and SUCNR1 downregulation.
- SUCNR1 activation promotes sprouting and tube formation in HUVECs from healthy pregnancies but not from GDM.
- GDM compromises SUCNR1-mediated modulation of angiogenic gene profiles in umbilical endothelium.
Clinical Implications
Although translational, findings suggest that modulating succinate signaling or restoring SUCNR1 responsiveness could improve placental vascularization in GDM. Biomarker development (succinate, SUCNR1 expression) may aid risk stratification.
Why It Matters
Identifies a novel metabolic signaling axis (succinate/SUCNR1) that modulates placental angiogenesis and is perturbed in GDM, offering mechanistic insight and potential therapeutic targets.
Limitations
- Causality in humans remains inferential; sample size and longitudinal follow-up details are limited
- Potential confounding metabolic changes in GDM not fully controlled
Future Directions
Validate succinate/SUCNR1 biomarkers in larger pregnancy cohorts; test pharmacologic or nutritional modulators of the succinate pathway to restore angiogenesis in relevant models.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- II - Observational human data integrated with mechanistic in vitro experiments
- Study Design
- OTHER