DALLAS – September 8, 2021 – A new study by scientists at UT Southwestern indicates that an enzyme called protein phosphatase 2 (PP2A) appears to be a major driver of preeclampsia, a dangerous complication of pregnancy characterized by the development of ‘high blood pressure and excess protein in the urine. The report, published in Traffic research, could lead to new treatments for preeclampsia other than preterm delivery, which is often the only option.
Philip W. Shaul, MD
“Preeclampsia is an unfortunately common cause of premature birth, which can put babies at risk and have lifelong consequences. By identifying the role of PP2A in this disease, we may be able to develop treatments for preeclampsia that are much better for mothers and babies, ”said study leader Philip W. Shaul, MD, professor. and Vice President of Research in the Department of Pediatrics at UTSW and Director of the Center for Lung and Vascular Biology. Dr Shaul co-led this study with Chieko Mineo, Ph.D., professor of pediatrics and cell biology.
Preeclampsia, which affects 5-7% of pregnant women worldwide, can be fatal for pregnant mothers and their babies and requires delivery at a premature stage.
Although the causes of preeclampsia are not well understood, explained Dr. Shaul, researchers have linked the disease to a variety of risk factors. One is an autoimmune disease known as antiphospholipid syndrome (APS), in which antibodies react to proteins on the surface of certain cells. Although PSA is relatively rare, affecting only about 5 in 100,000 people, studies have identified PSA antibodies in about 29% of pregnant women with preeclampsia.
To better understand how PSA leads to preeclampsia, Dr Shaul, Dr Mineo and their colleagues created an animal model by injecting PSA antibodies into pregnant mice. These animals developed high blood pressure and increased urinary protein, characteristic of preeclampsia. In contrast, PSA antibodies did not affect blood pressure in non-pregnant mice.
The images show how APS antibodies inhibit the migration of trophoblasts in the placenta of mice.
Based on previous work, the researchers knew that a protein called ApoER2 could be linked to the harmful actions of APS antibodies on placental cells called trophoblasts. These cells, which normally travel from the fetal side of the placenta to the maternal side to supply the fetus with nutrients, fail to make this connection in preeclampsia. In mice, APS antibodies prevented trophoblast migration and fetal growth was limited. When the researchers genetically engineered mice without ApoER2 into trophoblasts, the fetuses developed normally despite the APS antibody treatment and the mothers were protected against the development of preeclampsia.
But scientists knew ApoER2 wasn’t telling the whole story. They found that in the presence of APS antibodies, ApoER2 triggers the activity of PP2A, an enzyme that regulates protein functions throughout the body. Further experiments showed that in pregnant mice with APS antibodies, increased activity in PP2A increased the production of trophoblast proteins known to be involved in preeclampsia.
When the researchers gave pregnant mice a drug that inhibited PP2A, they were protected from preeclampsia and the treatment had no apparent harmful effects on the mice or their pregnant babies.
Hoping to translate these results to human patients, the scientists examined the placentas of women with PSA, finding that they too had increased PP2A activity. However, surprisingly, they found that compared to placentas from normal pregnancies, those from preeclampsia patients without PSA also exhibited increased PP2A activity, suggesting that this mechanism might work in various forms of preeclampsia. With further research, Dr Shaul said, treatments targeting PP2A or its related mechanisms in the trophoblast could possibly be viable treatments for preeclampsia in pregnant women.
Other UTSW researchers who contributed to this study include Haiyan Chu, Anastasia Sacharidou, An Nguyen, Chun Li, Ken L. Chambliss, Yu-Min Paul Shen, Julie Lo, Joachim Herz, Denise K. Marciano, Alina P. Montalbano, Xue Xiao, and Lin Xu.
This work was supported by grants from the National Institutes of Health (T32HL098040, R01HL109604, R01HD 094365, R01HL118001, R01HL147403, R37HL63762, R01NS093382, NS108115, RF1AG053391, 5R01HD100179-02), Canadian Institutes of Health Research (2012) 275374) CBBA-109624, American Heart Association / Harry S. Moss Heart Trust Postdoctoral Fellowship (18POST33960170), BrightFocus Foundation, Bluefield Project, Harrington Scholar-Innovator Award, Hartwell Foundation, Crystal Charity Ball Center for Pediatric Critical Care Research, and the Children’s Medical Center Foundation.
Dr Herz holds the Presbyterian Village North Foundation Honorary Chair in Therapeutic Research in Alzheimer’s Disease and the Thomas O. and Cinda Hicks Family Honorary Chair in Alzheimer’s Disease Research. . Dr. Marciano holds the Carolyn R. Bacon Distinguished Professor of Medical Sciences and Education. Dr Shaul holds the Associates First Capital Corporation Emeritus Chair in Pediatrics.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has been awarded six Nobel Prizes and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine and 13 researchers of the Howard Hughes Medical Institute. The full-time faculty of over 2,800 is responsible for revolutionary medical advancements and is committed to rapidly translating science-driven research into new clinical treatments. Doctors at UT Southwestern provide care in approximately 80 specialties to more than 117,000 inpatients, more than 360,000 emergency room cases and supervise nearly 3 million outpatient visits per year.