Enzyme may be a major driver of pre-eclampsia

Monday, 27 September, 2021

Enzyme may be a major driver of pre-eclampsia

Researchers at the University of Texas Southwestern Medical Center (UTSW) and other institutions have found that an enzyme called protein phosphatase 2 (PP2A) appears to be a major driver of pre-eclampsia, a dangerous pregnancy complication characterised by the development of high blood pressure and excess protein in the urine. Their finding, published in the journal Circulation Research, could lead to new treatments for pre-eclampsia other than premature delivery, which is often the only option.

Pre-eclampsia, which affects 5–7% of pregnant women worldwide, can be deadly for gestating mothers and their babies and requires delivery at a premature stage. Although the causes of pre-eclampsia aren’t well understood, researchers have linked the condition 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 some cells. Although APS is relatively rare, affecting only about five in every 100,000 people, studies have identified APS antibodies in about 29% of pregnant women with pre-eclampsia.

To better understand how APS leads to pre-eclampsia, researchers created an animal model by injecting pregnant mice with APS antibodies. These animals developed high blood pressure and a rise in urine protein, which are characteristics of pre-eclampsia. In contrast, the APS antibodies didn’t affect blood pressure in non-pregnant mice.

Based on previous work, the researchers knew that a protein called ApoER2 may be related to the harmful actions of APS antibodies on placental cells called trophoblasts. These cells, which normally journey from the foetal side of the placenta to the maternal side to provide the foetus with nutrients, don’t successfully make that connection in pre-eclampsia. In mice, the APS antibodies prevented trophoblast migration, and growth of the foetus was restricted. When the researchers genetically engineered mice without ApoER2 in trophoblasts, the foetuses developed normally despite APS antibody treatment, and the mothers were protected from developing pre-eclampsia.

But the scientists knew that ApoER2 didn’t tell the whole story. They found that in the presence of the APS antibodies, ApoER2 triggers the activity of PP2A, an enzyme that regulates protein functions throughout the body. Further experiments showed that in the pregnant mice with APS antibodies, heightened activity in PP2A increased trophoblast production of proteins known to be involved in pre-eclampsia. When the researchers gave the pregnant mice a drug that inhibits PP2A, they were protected from pre-eclampsia, and the treatment had no apparent harmful effects on the mice or their gestating babies.

Images shows how APS antibodies inhibit trophoblast migration in the mouse placenta.

Hoping to translate these findings to human patients, the scientists examined placentas from women with APS, finding that they too had increased activity of PP2A. However, in a surprising turn, they discovered that compared with placentas from normal pregnancies, those from pre-eclamptic patients without APS also had increased PP2A activity, suggesting that this mechanism could be operating in a variety of forms of pre-eclampsia.

“Pre-eclampsia is a regrettably common cause of premature birth, which can be life-threatening for babies and lead to lifelong consequences,” said study co-leader Dr Philip W Shaul, Director of UTSW’s Center for Pulmonary & Vascular Biology. With further research, Dr Shaul said, treatments targeting PP2A or its related machinery in the trophoblast may eventually be viable treatments for pre-eclampsia in pregnant women.

Top image credit: ©stock.adobe.com/au/Syda Productions

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