Acute NADPH Oxidase Inhibition Does Not Improve Microvascular Insulin- or Acetylcholine-Mediated Vasodilation in Women With a History of Gestational Diabetes Mellitus

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 and type 2 diabetes compared to healthy control (HC) women who had an uncomplicated pregnancy. Microvascular endothelial dysfunction, mediated in part by oxidative stress, persists after GDM and likely contributes to accelerated disease progression. Localized antioxidant treatment with ascorbate improves microvascular function after GDM; however, the molecular source(s) of reactive oxygen species (ROS) and their contribution to microvascular dysfunction after GDM have not been explored. We hypothesized that nicotinamide adenine dinucleotide phosphate oxidases (NOX), a source of ROS that contribute to endothelial dysfunction in diabetes, contribute to reduced microvascular insulin- and acetylcholine-mediated vasodilation in healthy women with a history of GDM. Women (n=10/group; GDM:33±8 years, 24±13 months postpartum; HC:33±5 years, 32±14 months post-partum) completed 2 intradermal microdialysis experiments: an insulin-dose response (10 -8 M-10 -4 M) to assess insulin-mediated dilation and an acetylcholine-dose response (10 -10 M-10 -1 M) to assess acetylcholine-mediated dilation. Four microdialysis fibers were placed in the dermal layer of the ventral forearm for the delivery of Lactated Ringer’s (control), L-NAME (nitric oxide (NO)-synthase inhibitor), apocynin (NOX-inhibitor), and L-NAME+apocynin. Red blood cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance (CVC=flux/mean arterial pressure) was normalized to maximum (%CVC max ). Insulin- and acetylcholine-mediated vasodilation were measured using the dose response area under the curve (AUC, %CVC max ). GDM had attenuated insulin-(GDM:24±7%CVC max vs. HC:53±12%CVC max , p =0.03) and acetylcholine-(GDM:198±34%CVC max vs. HC:277±27%CVC max , p =0.04) mediated vasodilation compared to HC. Apocynin did not augment insulin-(GDM:22±7%CVC max vs. Ringer’s, p =0.86; HC:27±11%CVC max vs. Ringer’s, p =0.07) or acetylcholine-(GDM:256±46%CVC max vs. Ringer’s, p =0.33; HC:265±28%CVC max vs. Ringer’s, p =0.82) mediated vasodilation in either group. There were no group or site differences in insulin- or acetylcholine-mediated vasodilation with NO-synthase inhibition (all p >0.05). Local NOX-inhibition did not improve insulin- or acetylcholine-mediated vasodilation, suggesting that alternative sources of ROS contribute to microvascular dysfunction following GDM. Future work investigating additional molecular sources of ROS and mechanisms of microvascular dysfunction in this high-risk cohort are warranted. NIH HL169201 This abstract was presented at the American Physiology Summit 2025 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.