# The role of oxidative stress in reduced microvascular function after gestational diabetes

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $588,858

## Abstract

PROJECT SUMMARY/ABSTRACT
Women with a history of gestational diabetes mellitus (GDM) are at a ~2-fold greater risk for cardiovascular
disease (CVD) and a ~7-fold greater risk for type II diabetes mellitus (T2DM) in the decade following
pregnancy, but the underlying cause(s) of this association are relatively unstudied, and there is a paucity of
trials evaluating preventive intervention to prevent or delay this onset of disease. Microvascular dysfunction
precedes and contributes to the development of CVD and insulin resistance in humans, via reductions in
endothelial-derived nitric oxide (NO) and insulin-mediated NO-dependent vascular responses, respectively. We
have demonstrated that endothelium- and nitric oxide-dependent dilation are attenuated in the
microvasculature of otherwise healthy women with a history of GDM and this reduction is mediated, in part, by
increased oxidative stress. However, the degree to which this attenuation in dilation extends to microvascular
insulin-mediated responses is unknown. Therefore, in aim 1, we propose a comprehensive examination of the
role of oxidative stress in attenuated microvascular endothelial insulin sensitivity in otherwise healthy women
who have had GDM. Our preliminary data suggest that nicotinamide adenine dinucleotide phosphate oxidase
(NADPH oxidase) contributes significantly to elevated reactive oxygen species after GDM, and that inhibiting
NADPH oxidase improves endothelial- and NO-dependent dilation, in vivo in these women. Therefore, in aim
2, we propose a comprehensive examination of the role of NADPH oxidase-derived reactive oxygen species --
which represent a future pharmacological target for the highly specific treatment and reversal of preclinical
vascular dysfunction after GDM -- in attenuated microvascular endothelial function in these women. Metformin
treatment improves vascular endothelial function and microvascular insulin sensitivity in patients at risk for
T2DM, in part through reductions in oxidative stress, suggesting that metformin treatment applied before the
onset of insulin resistance may improve microvascular endothelial responses in women with a history of GDM.
Therefore, in aim 3, we propose to examine the acute and chronic effects of metformin treatment on oxidative
stress-mediated mechanisms of microvascular dysfunction in otherwise healthy women with a history of GDM.
Overall, using an innovative translational human approach that combines in vivo pharmaco-dissection of
mechanisms of vascular function with the biochemical analysis of biopsied endothelial cells, the experiments
proposed herein will provide novel understanding of 1) early vascular mechanisms preceding the development
of overt cardiovascular and metabolic disease in women who have had GDM , and 2) mechanistically delineate
the efficacy of a readily available, safe, and inexpensive treatment to restore microvascular function before the
onset of disease in this high-risk cohort of women.

## Key facts

- **NIH application ID:** 10874693
- **Project number:** 5R01HL169201-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** ANNA STANHEWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,858
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874693

## Citation

> US National Institutes of Health, RePORTER application 10874693, The role of oxidative stress in reduced microvascular function after gestational diabetes (5R01HL169201-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10874693. Licensed CC0.

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