Clamping down on preeclampsia

A new discovery paves the way for a novel pre-eclampsia treatment...
06 February 2019


Drawing of human embryo


A breakthrough in understanding what causes pre-eclampsia in some pregnancies paves the way for a new treatment...

Pre-eclampsia affects 4-7% of pregnancies worldwide. Heralded by high blood pressure and the appearance of protein in urine from 20 weeks into a pregnancy, it can damage the kidney and liver, cause swelling in the brain and endanger the baby. Women showing the early-warning signs are closely monitored for the development of the more severe eclampsia and life-threatening seizures. Currently, the only way to relieve the symptoms is to deliver the baby, so doctors have to balance the risks to the mother against the costs to the baby of being born prematurely.

Now, work from Urusla Quitterer and her colleagues at ETH Zurich shows that abnormal signaling from a protein complex formed by two receptors called AT1 and B2, has a causal role in preeclampsia. Moreover, targeting the signals transmitted by these receptors may provide a way to prevent pre-eclampsia from progressing.

High blood pressure - or hypertension - in pre-eclampsia is linked to hypersensitivity to the hormone angiotensin II, which increases blood pressure by causing the smooth muscle cells lining blood vessels to contract, constricting the vessel. Hormones like angiotensin II act by binding to receptors on the surfaces of cells, and the angiotensin receptor on vascular smooth muscle cells is called AT1. But in preeclampsia, AT1 teams up abnormally with another receptor, called the B2 receptor, to form a receptor complex called AT1-B2.

Under normal conditions, the B2 receptor detects a blood-pressure regulating signal called bradykinin. But when the AT1 and the B2 receptors come together in the AT1-B2 complex, their three dimensional structure changes. This leads to an exaggerated cellular response to the normal angiotensin signal present in the blood. The AT1-B2 complex is also sensitive to mechanical stress, which could explain why the signs of preeclampsia, including hypertension, tend to appear only after 20 weeks of pregnancy, when the increasing weight of the baby places additional demands on the blood vessels in the placenta.

To explore whether the abnormal AT1-B2 complex can also cause the other manifestations of preeclampsia, the ETH team used genetic modification to express the complex in pregnant mice. This manipulation was sufficient to trigger in the animals all of the same signs seen in humans with preeclampsia. Encouragingly, the mice also revealed a way in which the condition might be managed. When a protein called ARRB1, which dampens signalling from the AT1-B2 complex, was expressed in these mice in an inactivation-resistant form, the increased ARRB1 activity prevented the development of preeclampsia. Together, these results suggest that abnormal signalling from AT1-B2 has a causal role in preeclampsia, a huge advance in our understanding of the disease.

The ETH team next investigated ways to target AT1-B2 signalling. TRV-027 is a small molecule which binds AT1-B2 and causes it to change its shape, encouraging ARRB1 to bind and negate the vasoconstricting effect. TRV-027 has been tested previously in humans for cardiovascular disease, and is not expected to cross placental barriers in large quantities. For these reasons it might turn out to be a promising lead in the management of what is a very common and important problem in pregnancy. Time will tell...


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