Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. It complicates 2-8% of all pregnancies today, and the incidence has been steadily increasing over almost 30 years. Preeclampsia is characterized by increased blood pressure along with one of a subset of signs of end-organ damage such as proteinuria after the 20th week of pregnancy. Although the precise etiology of preeclampsia is yet to be determined, widespread and persistent endothelial dysfunction has been shown to be a key contributing factor. Postpartum risk for cardiovascular disease has been established for women who develop preeclampsia, and emerging data on outcomes for offspring of affected pregnancies demonstrate a need for determination of the effect of this intrapartum environment on the fetus. The risks to such offspring have been well-characterized in humans; however, the mechanisms responsible for these risks remain unknown. Studies have demonstrated an increase in systolic blood pressure (BP) as early as nine years of age, increased salt sensitivity, and predisposition to a precipitous decrease in renal function after additional stressors such as high salt intake or pregnancy. Poorer metabolic profiles lend these children towards increased BMI and obesity. These risks ostensibly originate, at least in part, from the decreased uteroplacental perfusion present in the high-resistance, low-flow spiral arteries of preeclampsia. Our laboratory has previously characterized the Dahl salt- sensitive (S) rat as a spontaneous model of preeclampsia which will provide an ideal platform to study the long-term renal injury and endothelial function in offspring of affected pregnancies. We have also demonstrated improvement of uteroplacental flow and pup growth with the use of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, in the pregnant Dahl S rat. This project will test the central hypothesis that use of a PDE-5 inhibitor during preeclamptic pregnancy improves the long-term renal, vascular, and metabolic function of the offspring. This research will have significant impact on the field by 1) providing additional evidence of the long-term renal injury, endothelial dysfunction, and metabolic profiles of offspring of preeclamptic pregnancies and 2) demonstrating improvement thereof through use of a PDE-5 inhibitor during pregnancy. Therefore, this work has critical clinical and translational value as these findings could contribute to the establishment of preventive health assessment for offspring of affected pregnancies and provide evidence to support the use of PDE-5 inhibitors during preeclamptic pregnancy as a platform to improve long-term health of offspring.
Preeclampsia affects 2-8% of all pregnancies and increases the risk of renal injury and endothelial dysfunction in offspring of affected pregnancies. This proposal will use a spontaneous animal model of preeclampsia to explore long-term health risks to these offspring and the effect of intrapartum sildenafil administration.
