Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

A new study from the Smart group has shed light on a key regulatory step in the initiation and progression of Abdominal Aortic Aneurysm by revealing the protective role of a previously little known small protein.

A healthy aorta when compared with an aortic aneursm is significantly narrower and less swollen in appearance.

An abdominal aortic aneurysm (AAA) is a bulging of the aorta, the body’s main blood vessel, which runs from the heart down through the chest and stomach. Prevalence of AAA in the population is high, up to nearly 13% depending on age group, particularly for men aged 65 and over. An AAA can get bigger over time and rupture, causing life-threatening bleeding. There is a high mortality rate of around 80% in patients with ruptured AAA; only dropping to around 50% when patients undergo surgery.  

While clinicians can monitor the beginnings of AAA, a rupture can occur suddenly without warning. Currently, the only available intervention involves a high-risk surgical procedure, which is only undertaken if there is a real danger of rupture. There are no pharmacological treatment options because the underlying causes of AAA are not fully understood.   

Scientists know that in some patients there is a genetic predisposition to AAA, and large genomic studies have identified that mutations in a large protein called LRP1 predispose people to aortic aneurysm, as well as other major vascular diseases. However, the mechanism responsible for how these mutated genes cause the disease has so far been unknown. A new paper from the Smart Group has for the first time demonstrated that a smaller protein called Thymosin β4 (Tβ4) interacts with LRP1 and is ultimately responsible for the behaviour of the smooth muscle cells of the aorta.

Vascular smooth muscle cell differentiation is essential to the development of healthy blood vessels. The smooth muscle cells of the aorta play a crucial role in maintaining its stability and protecting it against disease. In their healthy contractile state, they provide strength and produce the elastin proteins to withstand forces and assist with pumping blood around the body. In disease, damage to the lining of the aorta causes accumulation of fat and allows immune cells to infiltrate vessel walls.  In response, the vessel attempts to repair itself and the smooth muscle cells try to make more smooth muscle. However, in doing so, the cells start to de-differentiate and become less contractile. According to lead researcher Associate Professor Nicola Smart: “They undergo proliferation, presumably with good intentions to try and make more smooth muscle, but actually it makes the problem worse. In doing so, they also break down the elastic layers that keep the vessels stable. These layers are supposed to hold the whole vessel together, keep it tight and keep it strong, and it all breaks apart.”

The reason the smooth muscle cells react in this way is due to their response to different growth factors that are released after injury. These growth factors (notably PDGF-BB) induce a ‘switch’ in the behaviour of the smooth muscle cells; from their contractile state to what’s known as their synthetic or ‘immature’ state, driving them to rapidly multiply and impairing their ability to produce the all-important elastic fibres to protect the aorta. However, it has never been fully understood how their response to the growth factor was controlled.

Through animal studies, the Smart group has found that Tβ4 interacts with LRP1 to control the trafficking of cell receptors for PDGF-BB. Receptors can either be destroyed through the cell’s waste disposal organelles, the lysosomes, which de-sensitises the cell to the effects of a growth factor, or they can be recycled back to the cell surface, which makes the cell more sensitive to the growth factor. Under ideal conditions, this is finely balanced to ensure the right number of receptors are at the cell surface. Tβ4 dictates whether receptors are recycled or degraded. If this protein is not present, too many receptors end up being recycled, the smooth muscle cell becomes hypersensitive and in essence overreacts.

This ultimately suggests that Tβ4 is the key to maintaining smooth muscle in its healthy contractile state, in cooperation with LRP1. Since Tβ4 dictates the fates of cell receptors, it causes a chain of events that determine the sensitivity of the smooth muscle cells in response to growth factors released in the beginnings of aortic aneurysm, and consequently the progression of the disease. Furthermore, Tβ4 is identified as a potential therapeutic target for treating AAA, since a reduction in levels of Tβ4 appears to be detrimental.

The larger protein LRP1 coordinates the growth cell receptors through distinct compartments within the cell for recycling or destruction.

Smooth muscle cell with LRP1/PDGRb trafficking through different subcellular compartments

The team were also able to compare their results with AAA samples from the Oxford Abdominal Aortic Aneurysm study. The OxAAA team surgically repair aneurysms in human patients, removing diseased tissue from the lining of the abdomen in the process. Through examining this, the Smart group were able to show that Tβ4 and LRP1 interact in both healthy and diseased patient vessels. Consequently, their study sheds light on a key regulatory step in AAA and identifies a promising new drug target to potentially treat the disease.

The full paper, first authored by Sonali Munshaw, “Thymosin β4 protects against aortic aneurysm via endocytic regulation of growth factor signaling” is available to read in The Journal of Clinical Investigation.

This story is featured on the Oxford Science Blog.

Similar stories

Reducing fat in the diabetic heart could improve recovery from heart attack

New research from the Heather Group has shown that in type 2 diabetes an overload of lipids reduces the heart’s ability to generate energy during a heart attack, decreasing chances of recovery.

The brain’s one-sided teaching signals

A new study by the Lak group reveals a novel facet of dopamine signalling during visual decision making.

Fellowship awarded to Huriye Atilgan to enhance our understanding of value-based decision-making

Congratulations are in order for Postdoctoral Research Scientist Dr Huriye Atilgan who has been awarded a prestigious Sir Henry Wellcome Postdoctoral Fellowship funded by the Wellcome Trust.

The future of stroke treatment

A team of international collaborators including DPAG's Dr Mootaz Salman has been researching a promising new therapeutic for the treatment of strokes and other brain injuries.

New review reveals proof of concept for an anti-obesity immunotherapy

The Domingos lab has published a new opinion piece in Science investigating the implications of a Memorial Sloan Kettering Cancer Center study that lays the foundations for a potential new anti-obesity treatment in the form of targeting adipose tissue-resident macrophages.