Scientists have found the root cause of pre-eclampsia The Guardian has reported. The newspaper said this could lead to treatments for the common but potentially serious complication of pregnancy.
This news story is based on research into the body’s production of angiotensin, a protein that constricts blood vessels and can therefore raise blood pressure. The researchers found that angiotensinogen, the the larger protein that is broken down to produce angiotensin, can exist in two forms, ‘oxidised’ and ‘reduced’.
Tests on 24 women revealed that those with pre-eclampsia had a higher proportion of the oxidised form than women who did not have pre-eclampsia during pregnancy. Oxidised angiotensinogen was more likely to be broken down to produce angiotensin than the reduced form.
The researchers suggest this may be one mechanism that raises blood pressure during pre-eclampsia. However, pre-eclampsia has other symptoms including protein in the urine and fluid retention, and this research does not suggest that changes in angiotensinogen causes pre-eclampsia, although it may contribute to the progression of this condition. These useful but early results will now need to be researched further.
The study was carried out by researchers from the University of Cambridge and The University of Nottingham. It was funded by The British Heart Foundation, The Wellcome Trust, The Isaac Newton Trust of the University of Cambridge and the UK Medical Research Council. The study was published in the peer-reviewed journal, Nature.
The Sun reported that pre-eclampsia was linked to levels of oxygen in the blood and that pregnant women are at greater risk of pre-eclampsia because their bodies take on extra oxygen to supply to their unborn babies. The research, however, did not look at this.
The Daily Telegraph reported that around 55,000 women die from pre-eclampsia every year. However, it should be pointed out that these are worldwide figures and the numbers of women who have serious pregnancy complications may vary from country to country.
The Daily Mail said that “angiotensins are usually hidden out of harm’s way deep inside a particular protein and it was not known what caused them to be released. The latest research fills this vital first step.”
It it already known how the larger protein angiotensinogen is cut by enzymes to produce angiotensin. What this research has found is a new way in which this known process is regulated.
This was a laboratory study that looked at the structure of a protein called angiotensinogen. Angiotensinogen is cut by an enzyme called renin, producing a smaller peptide called angiotensin I. Angiotensin I is further cut by an enzyme called the angiotensin-converting enzyme (ACE) to produce a smaller peptide called angiotensin II that constricts the blood vessels. Some blood pressure medication works by targeting the ACE enzyme to reduce the amount of angiotensin II released.
The researchers were interested in discovering the structure of angiotensinogen and whether it changed in conditions that mimicked pre-eclampsia, a pregnancy complication that is accompanied by high blood pressure. Pre-eclampsia has been associated with a type of chemical process known as ‘oxidative stress’ that occurs when the free-radical chemicals that are routinely produced by cells are not mopped up by the body’s antioxidants. This oxidative stress can cause chemical changes to proteins, fats and DNA in the cell.
The researchers created bacteria that contain the DNA sequence for making mouse, rat or human angiotensinogen. In this way they could use the bacteria to produce lots of the angiotensinogen protein, which could then be extracted and purified. The researchers then used a technique called X-ray crystallography to determine the shape of angiotensinogen.
The angiotensinogen protein was placed in different chemical conditions, as the researchers were interested in chemical conditions that would mimic oxidative stress and cause chemical changes to proteins.
They then used a technique called gel electrophoresis to separate different forms of the protein, and found there were two new forms of angiotensinogen present. These were an oxidised form (it had lost electrons) and a reduced form (gained electrons). The structure and behaviour of complex proteins can be altered by the loss or gain of electrons in this manor.
They then produced renin, the enzyme that digests angiotensinogen, and another protein called the prorenin receptor that facilitates the activity of rennin. They looked at how well it bound and how well it cut the oxidised and reduced forms of angiotensinogen.
Finally, they took samples from 24 women who had pre-eclampsia and 12 women who had normal blood pressure during pregnancy to see the proportion of reduced and oxidised angiotensinogen in their blood.
By looking at the crystal structure of the protein, the researchers found there were certain bonds that could be particularly vulnerable to chemical changes caused by oxidative stress. They found that these vulnerable bonds were broken when they created chemical conditions that mimicked oxidative stress.
The researchers found that they were able to detect both the oxidised and reduced form of angiotensinogen in blood samples. They found that the reduced-to-oxidised ratio of this protein was 40:60 and that this ratio did not change with age or gender.
The researchers also found that the oxidised form of angiotensinogen could bind better to renin during the cutting process and the enzyme was four times better at releasing angiotensin from oxidised angiotensinogen compared to reduced angiotensinogen.
They found that the samples from women with pre-eclampsia had a higher proportion of the oxidised form of angiotensinogen.
The researchers suggest that as the ability of renin to produce angiotensin from angiotensinogen is enhanced under chemical conditions that mimic oxidative stress. As angiotensin causes blood vessel changes this may provide a “causative link between the oxidative changes in pregnancy and the onset of high blood pressure that is a defining feature of pre-eclampsia”, they add.
This well-conducted, basic research found a new way that the proteins involved in regulating blood vessel constriction are themselves regulated. This research may be of particular relevance in pre-eclampsia as the researchers found that changes to angiotensinogen caused by oxidative stress (which may occur in pre-eclampsia) could lead to greater release of the angiotensin, the peptide that raises blood pressure by causing blood vessels to constrict.
They found a greater proportion of the oxidised angiotensinogen in women who had pre-eclampsia, which supports the theory that this mechanism may play a role in pre-eclampsia.
However, further research is needed to see whether oxidative changes in angiotensinogen would be sufficient to raise blood pressure in pre-eclampsia, and what triggers oxidative stress during pregnancy. At this stage it is not clear whether these changes to the ratio of oxidised-to-reduced angiotensinogen cause pre-eclampsia itself or simply a single symptom of pre-eclampsia.
Further research is also required to understand how angiotensinogen regulates blood pressure before deciding whether it is a suitable target for new drugs.
While the results of this research are compelling, raised blood pressure is only one initial symptom of pre-eclampsia. Pre-eclampsia is also characterised by other symptoms, namely protein in the urine and fluid retention. Equally, high blood pressure affects between 10-15% of all pregnancies, but is not always due to pre-eclampsia.
During antenatal appointments women will have the protein levels in their urine checked as well as their blood pressure, as a large amount of protein in the urine is a good indicator of the condition.