Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Vasoconstriction pathways are altered with insulin treatment in pregnancy: implications for understanding vascular dysfunction in gestational diabetes (#123)

Bianca R Fato 1 2 3 4 , Natasha de Alwis 1 2 3 4 , Sally Beard 1 2 3 4 , Natalie K Binder 1 2 3 4 , Tu'uhevaha Kaitu'u-Lino 1 2 4 , Natalie Hannan 1 2 3 4
  1. University of Melbourne, Parkville, VICTORIA, Australia
  2. Department of Obstetrics and Gynaecology , University of Melbourne, Parkville, Victoria, Australia
  3. Therapeutics Discovery and Vascular Function Group, Heidelberg, Victoria, Australia
  4. Mercy Hospital for Women, Heidelberg, Victoria, Australia

Gestational diabetes mellitus is a significant complication of pregnancy that is associated with maternal vascular dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction and vasoconstriction, however its regulation in gestational diabetes, and to a large extent in pregnancy, is unclear.

 

Circulating ET-1 was measured (ELISA) in plasma from patients with gestational diabetes (n=16), and gestation-matched controls (n=19). Human arteries were dissected from omental fat biopsies collected at caesarean section (n=28); gene expression of ET-1 and its receptors, ETA and ETB, were assessed (qPCR). Using wire myography, we investigated ET-1 artery constriction from patients with gestational diabetes, compared to gestation-matched controls (n=7). Diabetic cases were stratified by clinical management; diet (n=5) or insulin treatment (n=6). In further studies, arteries were pre-incubated with ETA and/or ETB antagonists (BQ123 and BQ788; n=7). We explored the effect of insulin by exposing healthy omental arteries (n=7) to insulin (10mU/mL) or vehicle. Additionally, healthy omental arteries were pre-treated with placental conditioned media containing high (25mM) or standard (5mM) glucose to model hyperglycaemia.

 

Circulating ET-1 levels and expression of ET-1, ETA, and ETB in omental arteries was not different in vasculature complicated by gestational diabetes. Interestingly, arteries treated with insulin during pregnancy demonstrated reduced ET-1 constriction compared to control, and diabetic diet managed pregnancies. Ex vivo short-term incubation of arteries with insulin showed reduced ET-1 constriction, suggesting insulin alters vasoactivity in pregnancy. Antagonising ETB receptors did not reduce arteriole ET-1 constriction in pregnancies treated with insulin, substantiating insulin treatment during pregnancy prevents vasoconstriction. Lastly, in models of placental hyperglycaemia no changes were detected in ET-1 driven constriction.

 

Insulin treatment during pregnancy reduces harmful ET-1 induced vasoconstriction. These data suggest that insulin modulates vasoconstrictor pathways and improves vascular function in gestational diabetes. Further investigation is needed to define the role of ET-1 in pregnancy.