Placental ischemia, the initiating event in preeclampsia (PE), is the leading cause of intrauterine growth restriction (IUGR) in the Western world. Numerous studies indicate that an increase in blood pressure (BP) is observed in individuals born following PE. Currently there are no effective drug treatments to prevent or treat PE and IUGR. The only treatment option for PE involves early delivery. Yet, birth before 37 weeks resulting in preterm or low birth weight (LBW) is also associated with increased BP in the offspring. Thus, there is a critical need to develop therapeutic perinatal interventions for the treatment of PE that not only improve maternal health but also mitigate fetal growth restriction and hypertension in the offspring. The well-characterized Reduced Uterine Perfusion Pressure (RUPP) model in the rat mimics the many facets of PE including pregnancy-specific hypertension. Additionally, the chronic excess sFlt-1 is another rodent model used to study the pathophysiology of PE. A common feature of these models is reduced fetal weight indicative of IUGR. Despite the different initiating events in these 2 models of PE, BP is in increased in male IUGR offspring in young adulthood. The Alexander laboratory reports that male IUGR offspring of RUPP dams exhibit an enhanced BP sensitivity to angiotensin II (ANG II) associated with an increase in the renal renin angiotensin system. BP is elevated and sensitivity to ANG II is also enhanced in female IUGR littermates in association with a loss of estrogen. Therefore, this proposal will use two clinically relevant models of IUGR to address the benefit of specific maternal interventions on fetal growth and hypertension in the offspring with a focus on ANG II and sex differences in BP risk. This proposal will also use a novel drug delivery technology to deliver maternally sequestered therapeutics to mitigate teratogenic effects while preventing the adverse consequences of placental ischemia on fetal growth and the fetal programming of increased BP in the offspring.
Specific Aim 1 will test the hypothesis that maternal therapeutic interventions improve uteroplacental perfusion and fetal growth mitigating increased blood pressure in IUGR offspring.
Specific Aim 2 will test the hypothesis that a reduction in enhanced sensitivity to ANG II in response to maternal therapeutic interventions mitigates the increase in blood pressure in IUGR offspring.
Specific Aim 3 will test the hypothesis that restriction of fetal exposure to maternal therapeutics provides protection against teratogenic outcome while retaining the benefit of improved fetal growth and reduced blood pressure in IUGR offspring.
Preeclampsia (PE) is the leading cause of intrauterine growth restriction (IUGR) in the Western world and results in an increase in blood pressure (BP) in the offspring. There is a critical need to develop therapeutic maternal interventions that not only improve maternal health in PE, but also mitigate fetal growth restriction and increased BP in the offspring. This proposal will determine if maternal interventions improve fetal growth and mitigate the increase in BP in the offspring of two well-established models of PE and IUGR.
| Reckelhoff, Jane F; Alexander, Barbara T (2018) Reproducibility in animal models of hypertension: a difficult problem. Biol Sex Differ 9:53 |
