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

Grace Maurer; Kara Whitaker; Diana Jalal; Anna Stanhewicz

doi:10.1152/physiol.2026.41.S1.2265565

Abstract only Despite a return to normal glucose tolerance after pregnancy, women with a history of gestational diabetes mellitus (GDM) have a greater risk of developing cardiovascular disease (CVD) compared to healthy control (HC) women who had an uncomplicated pregnancy. Microvascular endothelial dysfunction, mediated in part by reduced nitric oxide (NO)-dependent mechanisms, persists after GDM and likely contributes to vascular disease progression. Endothelin-1 (ET-1), a potent vasoconstrictor, contributes to vascular dysfunction in CVD and may similarly contribute to long-term vascular risk after GDM. However, the role of ET-1 in microvascular dysfunction after GDM has not been explored. 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 8 HC (36 ± 3 years, 35 ± 18 months postpartum) and 8 GDM (34 ± 3 years, 29 ± 17 months postpartum) women for the local delivery of lactated Ringer’s (control) or 500nM BQ-123 (ETAR antagonist) during a standard local heating protocol (42°C; 0.1°C·s-1). The local heaters remained at 42°C until skin blood flow plateaued (~40 minutes). Next, the sites were perfused with 15mM NG-nitro-l-arginine methyl ester (L-NAME, NO-synthase inhibitor; ~40 minutes) to quantify NO-dependent dilation. Red blood cell flux was continuously measured by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM sodium nitroprusside + local heat 43°C). The endothelium-dependent local heating plateau was attenuated at the Ringer’s site in GDM compared with HC women (GDM: 78 ± 35 vs. HC: 89 ± 11 %CVCmax; p=0.04). ETAR antagonism with BQ-123 increased the endothelium-dependent local heating plateau (87 ± 7 %CVCmax vs. Ringer’s; p=0.04) and NO contribution to the plateau (76 ± 7 vs. Ringer’s 66 ± 10 delta%CVCmax; p=0.02) in GDM women, but had no effect on the plateau (79 ± 18 %CVCmax vs. Ringer’s, p>0.05) or NO contribution to the plateau (67 ± 17 vs. Ringer’s 69 ± 6 delta%CVCmax, p>0.05) in HC women. Local ETAR antagonism improved cutaneous microvascular endothelium-dependent dilation. These improvements were mediated, in part, by an increase in NO-dependent mechanisms. These data suggest that ET-1 contributes to microvascular dysfunction following pregnancy complicated by GDM. NIH F31HL177925 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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

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