Endothelin-1 signaling in microvascular responses to insulin and the role of physical activity and sedentary behavior in women with a history of gestational diabetes mellitus

PROJECT SUMMARY/ABSTRACT The purpose of this Ruth L. Kirschstein National Research Service Award is to provide support for Grace Maurer, a Ph.D. student in Dr. Anna Stanhewicz’s laboratory at the University of Iowa, to conduct research that will prepare her to become an independent investigator in the field of maternal cardiovascular health. As part of her proposed training plan, she will learn a variety of new technical, conceptual, intellectual, and professional skills and refine research skills currently under development. Women who experience gestational diabetes mellitus (GDM) are 7 times more likely to develop type II diabetes and 2 times more likely to develop cardiovascular diseases than women who had an uncomplicated pregnancy. Microvascular dysfunction, mediated in part by decreases in the vasodilatory molecule nitric oxide, is likely a key mechanism contributing to reductions in microvascular insulin-mediated dilation and subsequent overt disease development in this population. Understanding the mechanistic underpinnings of this microvascular dysfunction prior to overt disease in this high-risk cohort of women is required to determine the pathophysiology of disease and identify mechanism-specific interventional approaches and is therefore an important biomedical research priority. Additionally, physical activity and sedentary behavior influence vascular function and disease risk in clinical populations (e.g. obesity, type II diabetes) but have not been mechanistically explored in healthy women with a history of GDM. Supported by strong scientific premise and compelling preliminary results, Grace will use an innovative human approach – leveraging the cutaneous circulation as an in vivo model of global microvascular function – coupled with device-based assessments of physical activity and sedentary behavior to determine the extent to which insulin-mediated endothelin-1 responses attenuate microvascular vasodilation in women with a history of GDM (Aim 1), and delineate the degree to which device-measured free-living physical activity and sedentary behavior predict microvascular endothelial responses to insulin in healthy control and GDM women (Aim 2). The proposed research will be the first to assess the mechanistic role of endothelin-1 on microvascular insulin-dependent responses and to examine physical activity and sedentary behavior and their impact on microvascular responses in women who had GDM after pregnancy but before overt disease development. This F31 fellowship project addresses important NHLBI research objectives to: 1) investigate newly discovered pathobiological mechanisms important to the onset and progression of heart, lung, blood, and sleep diseases, and 2) develop and optimize novel diagnostic and therapeutic strategies to prevent, treat, and cure heart, lung, blood, and sleep diseases. Under the expert supervision of her mentors, Grace will complete the proposed research and highly individualized training plan to advance a novel line of investigation and facilitate development towards becoming a successful independent investigator.