Preeclampsia is a condition in pregnancy that kills in the region of 70,000 mothers and 500,000 infants each year worldwide. It’s characterised by high blood pressure and excess protein in the urine after 20 weeks of pregnancy in a woman who previously had normal blood pressure. Left unchecked, the condition leads to serious complications: for the mother, damage to the kidneys and other organs; for the baby, growth restrictions as a result of a premature delivery.
Currently there is no cure for preeclampsia, but, thanks to the work of vascular biologist Professor Asif Ahmed and his team at Aston University, scientists are close to developing an effective treatment.
“Preeclampsia doesn’t just affect you during pregnancy, but its effect lingers on late into your life,” explains Professor Ahmed. “Women who have had preeclampsia are two times more likely to get other cardio-vascular diseases later in life. And it also has long-term effects on the baby because they’re at increased risk of getting heart disease.”
A Protein Imbalance
In the mid-1990s Professor Ahmed put forward a very new idea - that preeclampsia might be occurring because a protein (called vascular endothelial growth factor or VEGF) had become dysfunctional. VEGF is an angiogenic protein - in other words, it helps to create new blood vessels (for example, after injury, but also during embryonic development), and it also keeps blood-vessels dilated.
“I just speculated at that time that if VEGF is less active - maybe because there’s a rise in its natural inhibitor - you might get preeclampsia-like symptoms. But I had no evidence, it was pure speculation.”
Professor Ahmed’s hypothesis was backed up by developments in the treatment of cancer. Despite its positive role in creating new blood vessels, in some circumstances VEGF can also contribute to disease - in particular, to the growth of cancerous tumours. In tumour treatments it’s common to prescribe a therapy called Avastin, which inhibits VEGF, and therefore stops blood vessels from growing. However, as a result of taking Avastin, patients suffered from high blood pressure, the presence of proteins in the urine and kidney damage - all symptoms of preeclampsia.
With this evidence before them, scientists speculated that preeclampsia was in fact the result of an imbalance between two proteins: the angiogenic proteins (which make blood vessels) and the anti-angiogenic proteins (which inhibit them). In particular, a Boston group showed that clinical signs of preeclampsia may be due to the rise of the anti-angiogenic protein (sFlt-1) which inhibits VEGF.
As Professor Ahmed explains, it’s useful to think in terms of a racing car, which has lots of methods of controls, either for accelerating or braking. The act of inhibiting blood vessels - as with the cancer treatment Avastin - can have the result of accelerating the body until it crashes (this can be due to the increase of inflammation in the body, stress to proteins called oxidative stress, and imbalance of angiogenic milieu). If this is the case, then what would put a brake on the process and help it to restore balance?
Two Important Discoveries
Professor Ahmed’s lab discovered two potential brakes, the first being an enzyme called heme oxygenase. The Professor showed that statins (commonly used by people across Britain to lower cholesterol) inhibit anti-angiogenic proteins by inducing heme oxygenase-1, so the team concluded that statins could be successful in treating preeclampsia. The second, equally important, discovery by Professor Ahmed’s lab was another enzyme called cystathionine-gamma-lyase (CTH, also known as CSE) which produces hydrogen sulphide. Like heme oxygenase, it also helps to counteract problems caused by dysfunctional blood vessels.
“Here you have two potential enzymes which have been shown to be defective early in preeclampsia,” says Professor Ahmed. “So if you could restore their activity you would suppress the accelerators - the brake will go on and the damage will be less.”
Towards a Treatment
As a result of Professor Ahmed’s work, the first ever randomised controlled clinical trial (StAmP) was established for the use of statins in preeclampsia. Fifteen centres across England are taking part - all of which have been given legal and ethical approval to give statins to preeclampsic women. Although prescribing statins alone is unlikely to cure the condition, Professor Ahmed is optimistic that a treatment is now within grasp.
“We’ve been working on finding a cure for preeclampsia but I don’t believe it will be one thing. There’s never a magic bullet. Even statins, which people thought were a magic bullet, are not because one third of people don’t respond so well to them when they’re used for lowering cholesterol. It may be a cocktail of drugs. I don’t know yet. I think that we’re looking at a further five years of intensive research at least before we have developed an effective therapy for testing in a large population, but the fact that we’ve now recruited more than 50 patients and no-one has stopped the study gives me confidence that we’re on the right track.”
Praising the talented students and researchers who have supported his research, Professor Ahmed adds that he’s also indebted to the generosity of the British Heart Foundation and the Medical Research Council. “Their continued support is going to be important in ensuring that we can help doctors to transform the lives of women who suffer from preeclampsia and other pregnancy-related disorders.”