Cardiovascular disease remains a major public health problem and is the leading cause of death in the United States. Epidemiological data have illustrated that otherwise healthy women who develop preeclampsia during pregnancy are at a significantly (2-4 times) greater risk for the development of cardiovascular disease; however the mechanism(s) responsible for this association are unclear. One immerging hypothesis for this association is irreversible endothelial damage sustained during the preeclamptic pregnancy. Healthy women with a history of preeclamptic pregnancy demonstrate increased arterial stiffness and reduced endothelium- dependent vasodilation compared to women with a history of uncomplicated pregnancy, yet few, if any, human studies have sought to investigate the mechanism(s) responsible for this persistent vessel dysfunction. Rodent models of preeclampsia point to mechanistic roles for angiotensin II (ang II) and endothelin-1(ET-1) in the vessel dysfunction associated with preeclamptic pregnancy. These data suggest that changes in ang II and ET-1 signaling may lead to a pro-constrictor milieu in which attenuated endothelium-dependent vasodilation and reduced nitric oxide (NO) bioavailability result in exaggerated constriction and persistent vessel dysfunction following preeclamptic pregnancy. Therefore, the overarching goal of this proposal is to explore the mechanisms - both augmented constriction and attenuated endothelium-dependent dilation - by which ang II and ET-1 may contribute to this vessel dysfunction. We propose to utilize the human cutaneous circulation, a representative microvascular bed, to investigate microvascular signaling mechanisms in vivo in postpartum women who have had a preeclamptic pregnancy and postpartum control women who have had a normal pregnancy.
In specific aim 1 we hypothesize that women who have had a preeclamptic pregnancy will have an attenuated endothelium-dependent vasodilation response to local skin heating (physiological stimulus) and exogenous acetylcholine (pharmacological stimulus) compared to women who have had a healthy pregnancy.
In specific aim 2 we hypothesize that women who have had a preeclamptic pregnancy will have a greater vasoconstrictor response to exogenous ang II and ET-1 administration. Furthermore, we hypothesize that these alterations will be mediated by decreased NO bioavailability downstream of changes in ang II sensitivity and ET-1 receptor signaling. Intradermal microdialysis for the delivery of pharmacological agents directly to the cutaneous vascular bed, coupled with laser-Doppler flux for the measurement of cutaneous blood flow, will be used to pharmacodissect the proposed cellular mechanisms contributing to microvascular dysfunction in this population. This comprehensive assessment of the mechanisms that mediate the persistent microvascular dysfunction following preeclampsia directly translates the functional and molecular findings of cell and animal studies to a clinical population and will lend insight into the management of chronic elevated CVD risk in women who have suffered a preeclamptic pregnancy.
Women who develop preeclampsia during pregnancy are more likely to develop cardiovascular disease later in life, even if they are otherwise healthy. The reason why this occurs is unclear but may be related to blood vessel damage that occurs during the preeclamptic pregnancy and persists postpartum. The purpose of this investigation is to determine the mechanisms contributing to this blood vessel damage in women who have had preeclampsia. Identification of these mechanisms may lead to better clinical management of cardiovascular disease risk in these women.
| Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi et al. (2017) Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia. Hypertension 70:382-389 |
| Stanhewicz, Anna E; Kenney, W Larry (2017) Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev 75:61-70 |
| Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi et al. (2017) Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia. Clin Sci (Lond) 131:2777-2789 |
