Cinnamaldehyde mitigates placental vascular dysfunction of gestational diabetes and protects from the associated fetal hypoxia by modulating placental angiogenesis, metabolic activity and oxidative stress

Gestational diabetes mellitus (GDM) is a major pregnancy-related disorder with an increasing prevalence worldwide. GDM is associated with altered placental vascular functions and has severe consequences for fetal growth. There is no commonly accepted medication for GDM due to safety considerations. Actions of the currently limited therapeutic options focus exclusively on lowering the blood glucose level without paying attention to the altered placental vascular reactivity and remodelling. We used the fat-sucrose diet/streptozotocin (FSD/STZ) rat model of GDM to explore the efficacy of cinnamaldehyde (Ci; 20 mg/kg/day), a promising antidiabetic agent for GDM, and glyburide/metformin-HCl (Gly/Met; 0.6 + 100 mg/kg/day), as a reference drug for treatment of GDM, on the placenta structure and function at term pregnancy after their oral intake one week before mating onward. Through genome-wide transcriptome, biochemical, metabolome, metal analysis and histopathology we obtained an integrated understanding of their effects. GDM resulted in maternal and fetal hyperglycemia, fetal hyperinsulinemia and placental dysfunction with subsequent fetal anemia, hepatic iron deficiency and high serum erythropoietin level, reflecting fetal hypoxia. Differentially-regulated genes were overrepresented for pathways of angiogenesis, metabolic transporters and oxidative stress. Despite Ci and Gly/Met effectively alleviated the maternal and fetal glycemia, only Ci offered substantial protection from GDM-associated placental vasculopathy and prevented the fetal hypoxia. This was explained by Ci's impact on the molecular regulation of placental angiogenesis, metabolic activity and redox signaling. In conclusion, Ci provides a dual impact for the treatment of GDM at both maternal and fetal levels through its antidiabetic effect and the direct placental vasoprotective action. Lack of Gly/Met effectiveness to restore it's impaired functionality demonstrates the vital role of the placenta in developing efficient medications for GDM.