ROCHESTER, Minnesota — Pre-eclampsia, a life-threatening surge in blood pressure, is an enigmatic condition. Each year, it causes the deaths of more than 70,000 women worldwide. Because scientists do not know what causes it, they lack targeted strategies to treat it.
Delivery, the only available therapy, is not the cure it is often made out to be, according to Vesna D. Garovic, M.D., Ph.D., a nephrologist at Mayo Clinic in Rochester, Minnesota, who has devoted her career to studying this common pregnancy complication.
"Even after delivery, women can have dangerously high blood pressure for many days or weeks," she says. "And they remain at an elevated risk for cardiovascular and kidney disease decades later."
Through a combination of laboratory experiments and epidemiological studies, Dr. Garovic has shown that women with pre-eclampsia undergo a state of accelerated aging that propels them down the path of developing age-related conditions such as heart attack, stroke, and kidney failure.
Her research is unraveling a potential mechanism behind pre-eclampsia that could lead to the first therapeutics designed to treat an underlying cause of the condition. It also highlights the importance of increased screening and treatment for women with a history of pre-eclampsia.
Most pre-eclampsia research is based on the premise that the disease arises within the placenta, the organ that materializes with each pregnancy to protect and nurture the developing baby. Researchers believe that in pre-eclampsia, the placenta secretes molecules into the mother's circulatory system that cause inflammation and interfere with the formation of new blood vessels, a process known as angiogenesis. They believe that these nefarious molecules cause systemic disease in the pregnant person.
The goal has been to identify the molecule or molecules responsible, Dr. Garovic says.
For decades, researchers had noticed that placentas delivered from preeclamptic pregnancies often bore signs that they were aging faster than placentas delivered from normal pregnancies: "However, it was counterintuitive to say that pre-eclampsia was a disease of aging if you're looking at somebody who's 25 years old," Dr. Garovic says.
In fact, many of the molecules that were elevated in preeclamptic pregnancies were well-known markers of senescence, a cellular state that literally means "the process of growing old." Dr. Garovic theorized that senescence may be the pathway by which some women develop pre-eclampsia. Senescent cells stop dividing, but they do not die and are not always eliminated from the body. Instead, they sometimes accumulate in tissues and secrete harmful molecules.
Using samples and data from the Rochester Epidemiology Project, Dr. Garovic has tracked various signs of aging and senescence in women with and without preeclamptic pregnancies. Together with Mayo Clinic obstetrician-gynecologists Wendy White, M.D., and Yvonne Butler Tobah, M.D., she found that women who have had pre-eclampsia have a greater number of chronic conditions later in life—and develop these conditions at a much younger age—than those without a history of pre-eclampsia.
She also teamed up with Mayo Clinic cellular senescence experts James Kirkland, M.D., Ph.D., and Tamara Tchkonia, Ph.D., to show that women with pre-eclampsia undergo accelerated aging during pregnancy, as demonstrated by the "epigenetic clock." These epigenetic clocks enable researchers to calculate the biological aging of blood and other tissues by measuring the accumulation of methyl tags—which shift over time in any given organism—at hundreds of sites across the genome.
The researchers found that during their pregnancies and at the time of delivery, women with pre-eclampsia had aged an average of 2.4 years more quickly than women without the pregnancy complication.
Dr. Garovic holds out hope that new medications being developed in the field of senescence may one day prove to be safe for use during pregnancy, providing more options to women at risk.
Even if there are no specific treatments available right now to target senescent cells in women with a history of pre-eclampsia, Dr. Garovic believes research on the associations between this pregnancy complication and future health issues will have a big impact.
Her studies and others are already leading to new guidelines for the screening and treatment of women at risk, with the ultimate goal of improving outcomes and saving lives. For example, Dr. Garovic served on a working group for the American Heart Association examining hypertension in pregnancy and penned the association's scientific statement, which called for more work to protect women from complications of hypertensive pregnancies and possible post-pregnancy consequences.
"For women who have had pre-eclampsia, their blood pressure needs to be monitored, their cholesterol needs to be checked, their kidney function needs to be followed," she says. "We need to keep track of their BMI and weight and try to manage lifestyle modifications and their health long-term."
