Preclinical and clinical collaborators shed light on preeclampsia


Closeup of a pregnant woman's tummy.
Photo by Kathy West

By Jordana Lenon, Feb. 26, 2019

Preeclampsia is a medical condition that affects pregnant women, raising a mother’s blood pressure and threatening both her life and her baby’s. Accompanying symptoms include water retention and protein in the urine. Rarer, but more severe outcomes can include pain, headaches, nausea or even seizures, liver or kidney failure.

Most women can deliver a healthy baby if preeclampsia is detected early and treated with regular prenatal care.

No one knows the cause or how to prevent preeclampsia, yet two top-cited recent scientific reviews from long-time WNPRC scientific collaborators who have studied pregnancy health in both monkeys and women are providing some insights: A 2018 review reveals an emerging role for androgens in the pathogenesis of preeclampsia. A 2017 review describes the importance of the maternal vasculature to properly adapt to pregnancy to prevent preeclampsia and other hypertensive disorders.

University of Wisconsin–Madison researchers Sathish Kumar, Geoffrey Gordon, David Abbott and Jay Mishra published “Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis” in the October 16, 2018 issue of Reproduction (Cambridge, England). Specifically, the researchers discovered that testosterone levels in the circulation of preeclamptic women are elevated approximately two- to three-fold and positively correlate with vascular dysfunction. Preeclampsia is also associated with elevated placental androgen receptor (AR) gene expression, the authors found.

Furthermore, animal models of preeclampsia showed patterns and levels of increases in testosterone mimicking those found in women with the disorder. Studies have been able to replicate in monkeys the key features of preeclampsia, including gestational hypertension, endothelial dysfunction, placental hypoxia, decreased nutrient transport and fetal growth restriction.

“Taken together, the clinical and preclinical data strongly implicate androgen-mediated mechanisms as an important contributor to clinical preeclampsia,” says Kumar. He adds that novel compounds that inhibit excessive androgen action might be useful to reduce the severity of hypertension and endothelial dysfunction in preeclamptic patients.

“With these confirmed animal models of preeclampsia, we can now dig deeper to uncover the etiology and pathogenesis of preeclampsia, to gain a better understanding of the disorder and advance treatments and preventions for women,” Abbott adds.

A reading displayed on a blood pressure monitor

In another top-cited review on preeclampsia in the past two years, authors Derek Boeldt and Ian Bird, a long-time collaborator with Abbott, indicated that successful maternal vascular adaptation to pregnancy is critical to expand the capacity for blood flow through the placenta to meet the needs of the developing baby. Failure of the maternal vasculature to properly adapt can result in preeclampsia and other hypertensive disorders, the authors stated. This review, Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia,” appeared in the Journal of Endocrinology in 2017 and was among the top downloaded articles that year.

In scrutinizing studies for this review, the researchers focused on hormones that directly influence endothelial cell function and dysfunction, a hallmark of preeclampsia. Various growth factors and cytokines are present in pregnancies with normal vascular adaptation, but circulate at abnormal levels in preeclampsia pregnancies.

Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key calcium signaling events and chronically promoting the breakdown of endothelial cell-to-cell contacts, the authors stated.

“We’re beginning to understand how contributions of the placenta, immune cells and the endothelium itself promote a complex endocrine environment that leads to preeclampsia”, Bird says.

“To better treat this disorder, we need to focus on how different hormones may be acting together to create the conditions that lead to this disease,” Boeldt adds.

Sathish Kumar is an associate professor of comparative biosciences in the School of Veterinary Medicine and Jay Mishra is a postdoctoral research associate in his lab. Geoffrey Gordon is a physician at Unity Point Health in Madison and is also in the Department of Obstetrics and Gynecology in the UW-Madison School of Medicine and Public (SMPH). David Abbott is an SMPH professor of obstetrics and gynecology based at the Primate Center. Financial support for the Reproduction review came from the National Institute of Health (NIH) through grants HD069750, HL119869 and HL134779 (PI: S Kumar), as well as HD044405 (PI: A Dunaif) and HD028934 (PI: J Marshall) supporting D. Abbott.

Ian Bird is Vice Chair of Research, Director of the Reproductive Sciences Division and a tenured professor of obstetrics and gynecology in the School of Medicine and Public Health, He also directs the graduate student Endocrinology Reproductive Physiology Program (ERP). Derek Boeldt is an assistant professor of obstetrics and gynecology in the SMPH. He is both a former trainee and now a faculty trainer in the ERP. Financial support for the Journal of Endocrinology paper came from NIH grants (R03HD079856 and P01HD38843) as well as NIHT32HD041921 for predoctoral training for DSB. Additional training support for DSB was from University of Wisconsin SMPH Herman I Shapiro Distinguished Graduate Fellowship.