New signalling pathway to protect against hypertension discovered by Lund University researchers

By creating artificial ageing in mice, researchers at Lund University in Sweden have been able to track the formation of aneurysms in the walls of blood vessels. One finding of the study, now published in the Journal of Biological Chemistry, surprised the researchers: the mice were simultaneously protected against hypertension by activating a different signalling pathway in the cells of the vessel wall – compensating for the strain exerted on the ageing vessels. The findings create potential for future complementary blood pressure medicines.

In Sweden, around one in five people has high blood pressure. More research is needed to understand how and why high blood pressure damages blood vessels. It is well known that ageing makes blood vessels less flexible and more vulnerable. There is a risk of elevated blood pressure due to vascular stiffness. The strain of high blood pressure can cause an aortic aneurysm if things go awry.

The researchers behind the current article “Declining activity of serum response factor in aging aorta in relation to aneurysm progression” are Senior Lecturer and Associate Professor Catarina Rippe and Professor Karl Swärd, both at Lund University. In the current study, they have mapped all the genes that in healthy human arteries change with ageing. They then mimicked ageing in mice by knocking out a transcription factor – a protein that controls how genes are switched on or off in a cell – called serum response factor (SRF). SRF is a nuclear protein that controls gene expression in vascular smooth muscle cells. Just as the researchers had thought, when the SRF disappeared, the mice quickly developed early precursors of aneurysms.

In an earlier study from 2023, the authors, together with other Lund University researchers, found that the proteins YAP/TAZ, which are also known to decline with ageing, are essential for vessels to stay healthy. When YAP/TAZ was removed, the mice formed aneurysms in just a few weeks. The smooth muscle cells instead became cartilage-forming cells that caused inflammation and scarring. In the current study, YAP/TAZ also plays a pivotal role. When the transcription factor SRF was removed, the YAP/TAZ pathway was activated. This suggests that some kind of communication is established between SRF and YAP/TAZ. Karl Swärd draws an analogy with classical music.

“The SRF protein is the biggest composer of all, the one that is most important for the smooth muscle cell, indeed for the function of the entire vessel wall. The ageing super-composer is getting worse at writing new masterpieces. Then it’s like SRF, ‘Mozart’, telling YAP/TAZ that ‘you have to help me, Beethoven!’. In the study, we see that this communication is enabled by the enzyme LATS2. This is a surprising and internationally unprecedented finding,” says Karl Swärd.

The chain of reaction seems to be this: SRF goes down, causing LATS2 to decrease and thus activates YAP/TAZ. One of the properties of the LATS2 enzyme is that it switches off the activity of the YAP/TAZ double protein, which is already well known. So, as LATS2 declines, YAP/TAZ gets a chance to flourish.

“We thought the susceptibility to aneurysm would increase when we removed the SRF. But YAP/TAZ seems to compensate for this and protect the vessel wall, with the help of LATS2,” says Catarina Rippe.

In addition to the excitement of gaining a better understanding of biochemical processes, the researchers see pharmaceutical potential in the new results. Catarina Rippe’s focus is now on studying how to inhibit LATS2, which together with its sister enzyme LATS1 is needed to prevent the body from developing tumours, in a controlled and safe way. The LATS inhibitors developed by pharmaceutical companies so far inhibit both LATS1 and LATS2. The researchers therefore want to scientifically map and describe which variant of LATS2 is present in the vessel wall in order to specifically inhibit it. Later on, a vessel-specific knockout of LATS2 awaits, predicts Catarina Rippe.

“We hope to show that genetic LATS2 inhibition can protect against the vascular damage caused by hypertension.”

The discovery paves the way for new complementary blood pressure medicines, according to the researchers, but they believe this process will take at least five years.

“A strong point is that our results feel incredibly reproducible, and the impact is huge, for example, LATS2 increases almost 200-fold when we activate SRF. Our discoveries also provide new, important knowledge about how the vessel wall adapts to the mechanical forces exerted by blood pressure on the vessel wall,” says Karl Swärd.

Key facts about aneurysms

• An aortic aneurysm means that one or more pathological dilatations occur in the vessel wall of the body’s main artery.
• Aneurysms grow slowly and most sufferers are asymptomatic. The most easily detected aneurysms in the aorta are those found in the abdominal aorta. This condition is called abdominal aortic aneurysm or AAA.
• Sudden and severe pain, mainly in the abdomen, may signal that the aneurysm has grown significantly or ruptured. When the blood vessel in the abdomen bursts, symptoms are often acute. Severe back and abdominal pain is common, and the stomach may also become distended. Sometimes the pain radiates down to the groin.
• When the aorta ruptures in the chest, the pain is severe, both in the chest and in the back. The pain can be similar to – and be mistaken for – acute myocardial infarction (heart attack). In both cases, the person concerned will usually experience significant general symptoms. Nausea, vomiting, shock or fainting due to a drop in blood pressure and extensive blood loss are very common.
• A ruptured aortic aneurysm is a life-threatening condition. The rupture leads to major internal bleeding that requires immediate treatment. With today’s modern examination and treatment methods, doctors are able to save more and more people who arrive at the hospital in time. Early diagnosis and treatment improve the chances of survival.
• Risk factors include old age, being male, smoking, heredity, heart disease and high blood pressure. In Sweden, all 65-year-old men are invited to be screened for abdominal aortic aneurysm. This is done by ultrasound.

Source: Swedish Heart Lung Foundation