Abstract 4139148: Mechanisms of Maternal Cardiovascular Disease Development in a Novel Mouse Model of Pregnancy-Induced Diabetes

Background: Women with gestational diabetes mellitus (GDM) are more likely to develop cardiovascular disease (CVD) within 3 to 10 years following pregnancy. Endothelial dysfunction is a mechanism implicated in both hyperglycemia and CVDs, and it may constitute the missing link in this interaction. One reason for the lack of progress into the cardiovascular complications of GDM is the need for appropriate preclinical models that mimic human GDM. Also, the exact mechanisms mediating increased future cardiovascular risk in maternal with pregnancy-induced diabetes is unclear. Aim: To determine the mechanisms underlying cardiovascular disease in hormonal model of GDM. Methods: Sixteen week-old C57BL/6J female mice were treated with insulin receptor antagonist (S961) or saline (n=4) from the second trimester of pregnancy until delivery to develop a model of GDM. Glucose tolerance test was determined by glucometer and fasting insulin by colorimetry. Cardiac structure and function were measured by echocardiography (VEVO 3100) and pulse wave velocity was measured by Pulse Wave Doppler. Exercise tolerance test was performed on treadmill. Plasma endothelin-1 and nitrite were measured by ELISA and colorimetric assay. Aortic SIRT-1 was determined by western blot and aortic vascular reactivity was determined by wire myograph. Results: S961-induced GDM mice exhibit hyperglycemia (169.2 ± 3.6 vs. 105.5 ± 10.8mg/dL, P<0.004 ) and hyperinsulinemia (1.9 ± 0.2 vs. 0.8 ± 0.1ng/ml , p<0.01 ) which mimics the condition observed in human GDM. Interestingly, S961-induced GDM mice went on to develop systolic and diastolic dysfunction, vascular stiffness (3.7 ± 0.1 vs. 3.1 ± 0.08m/s, p<0.005 ), exercise intolerance and increased thickness of the cardiac wall at 10 weeks post-delivery. Plasma ET-1 was elevated in our model during pregnancy (28.1 ± 1.7 vs. 5.2 ± 0.2pg/ml, p<0.002 ) and at 10 weeks post-delivery (19.9 ± 2.9 vs. 6.7 ± 0.7pg/ml, p<0.05 ). Circulating NO and aortic expression of sirtuin-1 (SIRT 1), that is involved in endothelial longevity is reduced in GDM mice. Additionally, vascular relaxation to acetylcholine was attenuated in S961-induced GDM mice. Conclusion: We have developed a novel mouse model of GDM similar to that observed in pregnant women by treatment with S961. Moreover, S961 treated mice develop cardiac dysfunction and vascular stiffness at 10 weeks post-delivery. Alterations in ET-1, SIRT 1, and NO levels may be responsible for the development of CVD in this model.