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

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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.