Previous gestational diabetes impairs long-term endothelial function in a mouse model of complicated pregnancy

Women who develop gestational diabetes mellitis (GDM) display endothelial dysfunction up to 1 yr after pregnancy, despite a return to normoglycemia. It is unknown whether this dysfunction was preexisting or whether GDM pregnancy leads to long-term endothelial dysfunction. A mouse model that spontaneously develops GDM (Lepr(db/+)) was used to determine whether the endothelial dysfunction that develops during GDM is evident in later life. Heterozygous and wild-type (WT) controls were allowed to litter once, then age to 9-10 mo, and were compared with virgin controls. Vascular function of small mesenteric arteries was assessed using wire myography. Concentration response curves to the thromboxane A(2)mimetic U46619 and the endothelium-dependent vasodilator methacholine were constructed. Superoxide production and peroxynitrite formation was also measured. Mice with previous GDM displayed blood glucose concentrations similar to previously pregnant WT mice (8.0 +/- 0.1 vs. 7.1 +/- 0.3 mmol/l, P > 0.05). Arteries from mice with previous GDM displayed increased sensitivity to U46619 (EC(50) 5.2 +/- 0.7 vs. 45.2 +/- 1.0 nmol/l, P < 0.01) and impaired endothelium-dependent relaxation compared with WT controls (29 +/- 8 vs. 58 +/- 16 percent relaxation, P < 0.05). This was associated with increased superoxide production (93.3 +/- 2.3 vs. 64.6 +/- 1.6 mean fluorescence intensity, P < 0.001) and increased peroxynitrite formation (173.5 +/- 11.0 vs. 57.4 +/- 16.2 mean fluorescence intensity, P < 0.01) compared with virgin controls. In summary, endothelial dysfunction was evident in mice with previous GDM compared with previously healthy pregnant mice or virgin controls. These data suggest that GDM affects endothelial function and may contribute to an increased risk of cardiovascular disease.