Kumar Lab

Preeclampsia and Adverse Vascular Adaptations

It is unclear what pathophysiological mechanisms are involved in preventing normal vascular adaptations in certain pregnant women with preeclampsia and fetal growth restriction. Our lab focuses on the role of unhealthy lifestyles (e.g., high-fat or low-protein diets, stress, cigarette smoking, alcohol consumption), sleep disorders (e.g., sleep apnea, intermittent hypoxia), hormonal disruptions, infections, and environmental pollutants (e.g., PFASs) in causing the preeclampsia-like condition. We use animal models to examine if there are any common signaling mechanisms that mediate maternal vascular and angiogenic dysfunction.

One candidate is the androgen pathway -ten out of the twelve epidemiological studies show that testosterone levels are elevated in preeclamptic compared to normotensive pregnancies.

We found that the placental aromatase, the rate limiting enzyme converting androgens to estrogens is decreased in preeclampsia altering the equilibrium between estrogens and androgens in favor of androgens. We also showed that the expression of androgen receptor in the preeclamptic placenta is increased compared to normal pregnancies.

Our experimental studies in rats mimicking testosterone increase during pregnancy similar to that in preeclampsia, phenocopied essentially all symptoms of preeclampsia, including: increase in blood pressure, dysregulation in renin angiotensin system with increased AT1/AT2 receptor ratio and exaggerated vascular contractile responses to Ang II, proteinuria, endothelial dysfunction, altered angiogenesis, placental hypoxia and decreased spiral artery elongation, reduced placental nutrient transport capacity and fetal growth restriction.

Recently we have shown that environmental exposure to per- and polyfluoroalkyl substances (PFAS) affects maternal and fetal health. PFAS are a family of about 5,000 human-made non-biodegradable compounds present in air, drinking water, and food. The recent EPA Unregulated Contaminant Monitoring Rule 3 study reported that PFASs are detectable in 194 US public water systems that serve about 16.5 million people in 36 states and territories. Most water wells in Wisconsin and 25 other states have been reported to contain PFAS above EPA-prescribed levels. We analyzed PFAS levels in pregnant women admitted to the University of Wisconsin-Madison Department of Ob/Gyn and found that a range of 16 PFAS were detected in the maternal blood. Among the PFAS, perfluorooctane sulfonate (PFOS) was the most predominant. Administration of PFOS to pregnant rats caused a dose-dependent increase in maternal blood pressure along with a decrease in fetal weight. These growth-restricted babies born to PFOS-exposed dams developed hypertension when they grew into adults. Additionally, another stressor, gestational intermittent hypoxia (GIH), mimicking the sleep disorder of pregnancy, was found to program hypertension in offspring with a more pronounced effect in the males than females. Although, GIH results in development of hypertension in both prepubertal female offspring, after puberty, only male offspring remain hypertensive, whereas females become normotensive by 10 weeks of age. Ovariectomy negated the normalization of blood pressure and uncovered GIH-induced programming of hypertensive responses in female offspring suggesting that postpubertal estradiol contributes to the normalization of blood pressure in these animals. Currently, studies are underway to identify the molecular mechanisms by which PFASs and GIH affect maternal and fetal health.