The influence of pregnancy on future vascular dysfunction and atherosclerosis
PI: Robert W. Powers, PhD
Magee-Womens Research Institute and Foundation
Department of Medicine
The focus of this proposal investigates fundamental questions regarding the effect of pregnancy and pregnancyspecific hypertension (preeclampsia) on future maternal vascular health. Heart disease is the leading cause of death among women in the United States, affecting one out of three women. The risk of future cardiovascular disease (CVD) among women with previous preeclampsia is 2 to 8 times more than that of women with previous uncomplicated pregnancies. However, the mechanism(s) linking adverse pregnancy outcomes such as preeclampsia and future CVD are unclear. Furthermore, epidemiologic data indicates uncomplicated pregnancy alone is also associated with an increased risk of future CVD compared to never pregnant women.
We are directly investigating these epidemiologic findings using specific mouse models, the pro-atherogenic hypercholesterolemic apoE-/- mouse model and the C1q pregnancy-specific hypertension mouse model that mirrors preeclampsia. Specifically, we hypothesize: 1. Pregnancy-specific hypertension leads to maternal vascular stress with effects that persist postpartum and elevate the risk of future vascular dysfunction and atherosclerosis. 2. Pregnancy increases the risk and hastens development of future vascular dysfunction and atherosclerosis. In addition, we have been focused on the role of asymmetric dimethylarginine (ADMA) as a novel and significant independent risk factor for CVD. The adverse effects of ADMA may be overcome by increasing levels of the amino acid L-arginine, thereby increasing the Arginine/ADMA ratio.
We have important preliminary data that indicates maternal supplementation with the amino acid L-citrulline, which is readily converted to L-arginine, in early pregnancy significantly increases the Arginine/ADMA ratio, improves vascular function, decreases maternal blood pressure and increases circulating levels of PlGF and decreases sFLT1, suggesting improved placentation. Therefore, we further hypothesize 3. the nutraceutical L-citrulline will significantly increase the Arginine/ADMA ratio, improve placentation, decrease blood pressure, and blunt atherosclerosis progression in apoE-/- and the C1q pregnancy-specific hypertension model. This proposal contributes to direct evidence supporting or refuting epidemiologic studies regarding the effect of pregnancy and preeclampsia on maternal future cardiovascular health.