Researchers have proposed a new therapy for preeclampsia that corrects the defects identified in placental cells, and restores placental and foetal weight, which they report in the journal Redox Biology. The treatment, tested in two rodent models, successfully lowers blood pressure in the mother and resolves the characteristic preeclampsia symptoms of proteinuria and cardiovascular abnormalities.
Preeclampsia is a placental dysfunction that affects approximately 2 to 8% of pregnant women worldwide. It can have potentially complications for mother and child, and longer-term consequences for the mother. Preeclampsia symptoms are primarily arterial hypertension, proteinuria, abnormal coagulation in the placenta, cardiovascular abnormalities in the mother and foetal growth restriction. Treatments for preeclampsia are limited and mostly involve aspirin as a preventative measure, reducing the procoagulant state in the placenta and partly relieving pressure on the vascular network.
Preeclampsia is characterised by a defective placenta caused by trophoblast dysfunction. Trophoblasts are placental cells that help organise and manage the vascular network which provides the essential resources for foetal growth. At the molecular level, preeclampsia is characterised by an uncontrolled increase in oxidative stress, with excessive production of various reactive species including reactive oxygen and nitrogen species. There is a genetic component: the first gene to be identified as being implicated in the genetic forms of preeclampsia was the STOX1 transcription factor, which controls the expression of thousands of genes, especially those involved in the production of nitric oxide (NO).
In a transgenic mouse model, high accumulation of STOX1 in the placenta induced a preeclampsia-like syndrome. In preeclampsia, NO, a powerful vasodilator that promotes blood flow to the placenta, is mobilised to produce potentially toxic molecules (nitrosative stress) and its levels become insufficient in the placental vascular network, affecting trophoblast function and the vascular network and destabilising other reactive species. This creates a vicious circle and causes uncontrollable oxidative/nitrosative stress with multiple complications, also affecting maternal blood vessel cells, with potentially fatal consequences.
NO is produced by a family of enzymes known as nitric oxide synthases (NOSs). Finding a way of restoring NO production in the placenta via NOSs could represent an effective new therapy to treat preeclampsia. A years-long collaboration gave rise to a potential solution. The scientists’ research was based on trophoblasts overexpressing STOX1 and on two rodent models of preeclampsia, one mimicking early-onset forms via placental overexpression of STOX1 and the other mimicking late-onset forms by partial occlusion of the lower abdominal aorta.
The research revealed a cascade of events that ultimately led the scientists to propose a new therapy. Treating trophoblasts with BH4 (tetrahydrobiopterin, a cofactor that stabilises the NOS enzyme producing NO) corrected the defects identified in these cells, restoring production of NO rather than potentially toxic molecules. More importantly, administering BH4 to the two preclinical rodent models restored placental and foetal weight. Finally, in the early-onset STOX1 preclinical model with significant arterial hypertension and proteinuria, the BH4 treatment corrected blood pressure, excess protein in urine, and cardiovascular abnormalities in the mother. The results even suggest that the treatment may be effective in addressing the long-term effects of preeclampsia on mothers (vascular abnormalities in the brain, kidneys, heart and liver).
This research is the first step towards the development of a therapy for preeclampsia. Genetic analyses of placentas treated with BH4 showed that it corrects the expression of several genes disrupted by excess STOX1 differently than the deregulation induced by aspirin in the placenta. The scientists therefore propose that a treatment combining BH4 and aspirin could be the ultimate therapeutic solution for many cases of preeclampsia. This hypothesis needs to be validated in clinical trials.
Source: Institut Pasteur
