“Getting rid of stress is death”: why stress causes hypertension Biologist Markel explains why personalized hypertension treatment is important

– How acute is the problem of combating hypertension for medicine at the moment?

– The problem is urgent. About a quarter of the world’s population, up to half in some countries, suffers from hypertension, and 20% of patients manage to control their blood pressure despite multiple medications. And literally one out of every two people closer to old age has high blood pressure. If we consider the normal pressure as 120 to 80, however, people who have it still need to be sought. It is important to change the way of life, change the behavior – few achieve this. Medicines don’t always help either. For this reason, cardiovascular diseases keep the first place in terms of death and the most common of these diseases is hypertension.

Stress is considered one of the main causes of hypertension. Why does it raise blood pressure?

It occurs under conditions of stress, danger or uncertainty. Any environmental influence that causes an unusual situation is associated with stress, sometimes causing joy. They were promoted – and the pressure increased.

Pressure increases during stress to increase the perfusion of organs with blood. The higher the pressure, the more active the blood flow to the organs, including the brain – and this is a very energy-intensive organ, it spends more than 20% of the energy consumed at rest. So stress is necessary. Getting rid of stress is death.

But the trick is to deliberately increase the pressure, at the right time, in the right place. Also, the change in blood flow can be local – somewhere more or less. All this is regulated by the nervous system.

– So, is this such an emergency response mechanism?

– Of course. And this is a very complex system with direct and feedback connections with some side connection configurations. When it fails, the problems begin. For example, a normal pressure drop is required in people at night, whereas in hypertensive patients this usually does not happen. With chronic stress, this system starts to work as if on its own, and the pressure rises even when it is not needed. The blood flow to the organs does not need to be increased, but the heart pumps blood, the pressure rises.

“Now, every decade or so, life is getting better fed and safer, and more and more people are talking about stress. Is it really growing?

– Primitive man also had enough stress, but they reacted to it in a natural way – run or fight. And we cannot escape. And we can’t fight. So we digest it all. Aboriginal peoples who lived mainly in the Stone Age do not have hypertension. But we civilized people have it. Civilization has actually evolved over the last 10 thousand years. And in these 10,000 years, our living conditions have changed so dramatically, they are now very different from those of our ancestors.

And the genome can’t keep up with this evolution of the environment. Mutations are rare and are random, not intentional. Therefore, as they say, we came out of the Stone Age, but the Stone Age did not come out of us.

We found ourselves in a completely different situation: in the vast majority of cases there is no direct threat to life, and stress now has more of an emotional, social connotation. And responses to it have been preserved – the environment has changed so dramatically that the genome can’t keep up.

And more importantly: our ancestors ate fresh food, mostly vegetables, in everyday life there was no salt. For this reason, a very powerful salt storage system has been formed in our body for millions of years. And he developed a food addiction to salt in humans. Then a lot of salt appeared – and now we add salt to everything, it tastes good to us, and by the way, salt accumulates in the body. This leads to the accumulation of fluid, an increase in blood volume and, accordingly, an increase in pressure.

– For research, you have bred a special breed of mouse that is genetically prone to high blood pressure. But is hypertension a matter of heredity, not lifestyle and exposure to stress?

– Stress is stress, but any response depends on the characteristics of the body. And these traits are genetically determined. Therefore, some people – or mice – react strongly while others do not.

Stress is a trigger, but what exactly it triggers depends on the genome.

The genetic basis of hypertension is quite complex. First of all, this includes the genes responsible for ion metabolism. Another role is played by genes that regulate the functioning of the immune system – inflammatory reactions affect the risk of developing hypertension. So far, no one knows all the genes associated with pressure increase. And then there are the interactions between genes, one gene enhances or suppresses the work of the others.

Hypertension is a very complex disease. And isolating the genetic makeup, the genetic network that causes a persistent increase in blood pressure in each particular case, is quite a challenge. Few have had great success in this direction. Moreover, unlike linear animals, rats and mice, human populations are very heterogeneous genetically and phenotypically. In linear animals, it is easier to identify candidate genes that are causative factors of disease.

Any reaction occurs when the genotype interacts with the environment. Therefore, with the help of selection, we created such a genetic model of hypertension – mice with almost the same genome, genetically predisposed to increased pressure under stress.

The stress factor for rats is the same – we put them in a small cage that restricts movement. This is called restraint – mice are not completely motionless, but they cannot escape anywhere.

Even now, issues of epigenetic regulation of blood pressure are widely studied – that is, when the activity of genes changes without changing their primary sequence. Epigenetics has a very serious impact, especially when the organism rapidly transitions from an ordinary to an unusual state and the genome cannot adapt by changing the primary sequence.

Why can’t we adapt to chronic stress? So that high blood pressure becomes the norm and does not cause health problems?

– When I selected mice for increased pressure during stress, it should have been normal at rest. However, it was later revealed that it also increased at rest in many mice. What is he saying? In the selection process, the genes that determine the stress response somehow interact with or are associated with the genes responsible for the resting response. British scientist Conrad Waddington introduced the concept of genetic assimilation – this is when an acquired trait is fixed in a population as a result of genetic selection. Due to the lack of a transverse vein on the wing, the fruit fly himself directed the selection. Fly pupae are absent when exposed to heat shock and stress. And with the help of selecting flies that are prone to such a response to stress, it was possible to ensure that even without heat shock this transverse vein in the wing was absent. That is, the genes were selected in such a way that the trait became constitutive, which is already inherent in the normal genome.

Of course, such drastic changes cannot happen in a person’s life. And even in the entire population – this is unlikely: after all, people are not subjected to such purposeful strict selection.

– In studies planned for 2022-2024, your research group plans to examine genes that regulate high blood pressure during stress and seek new molecular targets for diagnosis and treatment. What about genetic therapy for hypertension?

— No, we will not interfere with the genome, it is dangerous. Molecular targets are what hypertension drugs act on. Those with elderly relatives are familiar with such drugs – ACE enzyme blockers (captopril), type 1 angiotensin receptor blockers (losartan), etc. And the truth is that all people are treated equally. There are many drugs for hypertension, but everyone is prescribed basically the same drugs, they act at certain endpoints in the blood pressure regulation circuit and do not allow the pressure to rise. And the drug must be taken constantly.

And in order to find links in this chain of reactions that can be affected, we want to understand how it all started, what initially led to the pressure increase.

Also, to act prophylactically so that hypertension does not develop at all. This is an unresolved issue yet.

But our mice have the same genotype, and all humans are different, all genomes are different. Accordingly, the molecular targets may also be different. Therefore, there is another direction – looking for genetic markers to point to these targets. Or metabolic markers. All this will make it possible for the patient to individually select drugs that will extinguish the disease on the way, depending on its genotype.

– A common problem in animal studies is that the results obtained cannot be subsequently replicated in humans. How transferable are studies of hypertension in rats to a human model?

“They’re well tolerated because the blood pressure regulation system in mice and humans is pretty much the same. And the pressure is the same – 120 vs 80. The problem is different – human studies are much more expensive, they require very serious funding. And even if the study is clearly promising, it’s hard to achieve. And this issue needs to be addressed because people need to be treated.We’re going to cure the mice somehow.