Gestational diabetes promotes future maternal cardiovascular disease through endothelin activation and suppressed NO/cGMP/PRKG and AMPK/SIRT1 signaling pathways

Women with gestational diabetes mellitus (GDM) are more likely to develop cardiovascular disease (CVD) within 3 to 10 years following pregnancy. Despite a return to normoglycemia shortly after gestation, GDM mothers still possess an increased risk of future CVD. In this study, we use a novel preclinical hormonal model of GDM to examine the mechanisms underlying future vascular and cardiac dysfunction in mothers with a history of GDM. We treated 16-week-old pregnant C57BL/6J mice with the insulin receptor antagonist (S961; 30nmol/kg, s.c.) from gestational day (GD) 7 (second trimester of pregnancy) until delivery to induce GDM. GDM mice developed systolic and diastolic dysfunction, arterial stiffness, hypertension, increased cardiac mass, and exercise intolerance at 10 weeks postpartum compared with saline-treated pregnant or S961-treated virgin mice. We also observed decreased plasma nitric oxide (NO) and increased endothelin-1 (ET-1) in GDM. The aorta of S961-induced GDM mice had increased pulse wave velocity, impaired vascular relaxation, remodeling, elevated reactive oxygen species (ROS) production and adhesion molecules, increased ET-1 type A receptor expression, and reduced sirtuin-1 (SIRT-1) expression. The left ventricle of S961-induced GDM mice exhibited fibrosis, thickness, and increased ROS production. Additionally, alterations in cardiac kinase activity in the nitric oxide/cyclic guanosine monophosphate/protein kinase G (NO/cGMP/PRKG) and AMP-activated protein kinase (AMPK) alpha pathways were observed at 10 weeks postpartum using novel Pamgene kinome technology. Thus, endothelin activation, suppressed NO/cGMP/PRKG signaling, impaired AMPK, and altered SIRT1 may be responsible for the development of vascular stiffness and cardiac dysfunction in mothers with a history of GDM.