Preeclampsia is estimated to affect 5-7% of all pregnancies in the U.S. Hypertension associated with PE develops during pregnancy and remits after parturition implicating the placenta as a central culprit in the disease. The initiating even in PE is postulated to involve reduced placental perfusion that leads to widespread maternal vascular endothelial dysfunction by mechanisms involving the placental release of antiangiogenic factors such as sFlt-1, which antagonizes endogenous vascular endothelial growth factor (VEGF) and placental growth factor (PlGF);inflammatory cytokines such as tumor necrosis factor (TNF ?);and reactive oxygen species (ROS). Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia, and current management therapies have significant limitations. Based on recent studies and on preliminary data presented in this application, we propose that, phosphodiesterase-5 inhibitors may provide a novel therapeutic approach for the treatment of preeclampsia and the cardiovascular consequences in the low birthweight offspring. Based on our exciting preliminary data, we propose to test the central hypothesis that PDE5 inhibitors attenuate the blood pressure and renal responses to placental ischemia in pregnant rats by inhibition of sFlt-l production. In addition, we propose that PDE5 inhibitors improve renal function and decrease total peripheral resistance and blood pressure by inhibiting the placental production of TNF and reactive oxygen species (ROS) and attenuating TNF? and sFlt-1-induced increases in production of endothelin (ET-1). Moreover, we propose that PDE5 inhibitors will attenuate the hypertension in low birth weight offspring of placental ischemic rats. To test this hypothesis, arterial pressure, renal function, and endothelial factors will be examined in a conscious, chronically instrumented rat model of PE produced by long-term reductions in uterine perfusion pressure (RUPP). In addition, our placental insufficiency model of IUGR will be used to examine the effects of PDE5 inhibitors on cardiovascular function in the low birthweight offspring.
Specific aims are: 1) To test the hypothesis that phosphodiesterase-5 inhibitors attenuate the blood pressure, renal, and sFlt-1 responses to placental ischemia in pregnant rats 2) To test the hypothesis that phosphodiesterase-5 inhibitors attenuate the reactive oxygen species and TNF responses to placental ischemia 3) To test the hypothesis that phosphodiesterase-5 inhibitors decreases blood pressure in low birth weight offspring of placental ischemic rats.

Public Health Relevance

Hypertension and IUGR, as seen in preeclampsia (PE), has long been recognized as a major risk factor for cardiovascular diseases. Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent PE. Based on preliminary data presented in this application, we propose that Phosphodiesterase-5 inhibitors may provide a novel therapeutic approach for the treatment of PE and IUGR.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL109763-02
Application #
8518448
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitchell, Megan S
Project Start
2012-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$213,486
Indirect Cost
$70,686
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
George, Eric M; Palei, Ana C; Dent, Edward A et al. (2013) Sildenafil attenuates placental ischemia-induced hypertension. Am J Physiol Regul Integr Comp Physiol 305:R397-403
Palei, Ana C T; Granger, Joey P; Tanus-Santos, Jose E (2013) Matrix metalloproteinases as drug targets in preeclampsia. Curr Drug Targets 14:325-34