Local endothelin-1 receptor type A antagonism improves cutaneous microvascular function in women with a history of gestational diabetes mellitus.

Women with a history of gestational diabetes mellitus (GDM) are at a greater risk of developing cardiovascular disease (CVD) compared to women who had an uncomplicated pregnancy. Microvascular endothelial dysfunction, mediated in part by reduced nitric oxide (NO)-dependent mechanisms, persists after GDM and contributes to vascular disease progression. Endothelin-1 (ET-1), a potent vasoconstrictor, contributes to vascular dysfunction in diabetes and may similarly contribute to vascular dysfunction after GDM. We hypothesized that local ET-1 receptor type A (ETAR) antagonism would improve endothelium- and NO-dependent dilation in the cutaneous microvasculature of women with a history of GDM. Two intradermal microdialysis fibers were placed in the skin of the ventral forearm of 12 healthy controls (HC, 35 ± 3 years) and 12 women with a history of GDM (34 ± 4 years) for the local delivery of lactated Ringer's (control) or 500nmol/L BQ-123 (ETAR antagonist) during a standard local heating protocol (42°C; 0.1°C·s-1). After full expression of the local heating response, 15mmol/L NG-nitro-L-arginine methyl ester (NO synthase inhibitor) was perfused. Red blood cell flux was measured by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (28mmol/L sodium nitroprusside + 43°C). Endothelium- (p=0.04) and NO-dependent (p=0.03) dilation were attenuated at the Ringer's site in GDM compared with HC women. In GDM women, ETAR antagonism increased endothelium- (vs. Ringer's; p=0.03) and NO-dependent (vs. Ringer's; p=0.01) dilation but had no effect in HC (p>0.05). These data suggest that ET-1 contributes to microvascular dysfunction following pregnancy complicated by GDM.