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Schematic of plexin D1 receptor

A study led by RDM researchers has discovered the molecular ‘first responder’ which detects disturbances in the flow of blood through the arteries, and responds by encouraging the formation of plaques which can lead to serious problems, including heart attack, stroke and even death. The study, published in the journal Nature, found that mice without this molecule in its right shape don’t have clogged arteries, even when they eat an unhealthy high fat diet.

Atherosclerosis is a potentially fatal disease where fatty plaques clog up the arteries supplying blood to the heart, brain and other organs. These plaques cause the arteries to narrow and can increase the risk of blood clots that could block blood flow to the heart or brain, making it more likely that patients with atherosclerosis will suffer from heart attacks or strokes.

But scientists have known for over 200 years that the plaques don’t form just anywhere in the arteries – they are much more likely to form where the arteries curve or split, causing whorls and eddies in the blood flowing through them.

“The blood flowing through our arteries is like a river,”
- Dr Ellie Tzima

“The blood flowing through our arteries is like a river,” said Associate Professor Ellie Tzima, who led the study. “Straight areas of this blood river are protected from the formation of plaques, but where this river bends is where we get chronic inflammation, eventually leading to formation of potentially life-threatening plaques.”

While scientists have previously discovered ‘mechanosensor’ molecules which can detect disturbed blood flow, researchers did not know the exact molecular details of what sets off the cascade of inflammation that leads to atherosclerotic plaques.

Finding the sensor

Now a team of researchers from Oxford University, Imperial College London, Duke University and the University of Chicago have found that a protein called Plexin D1 not only senses disturbances in the smooth flow of blood, but also then sets of a complex chain of events that kick starts inflammation and plaque formation at that site.

Dr Ellie Tzima, who is a Wellcome Senior Fellow at Oxford University’s Radcliffe Department of Medicine, said: “We used very tiny magnetic ‘tweezers’ to pull on the Plexin D1 protein, and we found that it responded to the pulling force by releasing signals that start a domino effect, ultimately resulting in plaque that can go on to cause a heart attack.”

The research team also found that Plexin D1 folds into a closed, ring-like shape, or an open, chair-like shape: only the chair-like shape responded to the magnetic tweezers pull.

What’s more, genetically engineered cells that only have ring-shaped Plexin D1 did not respond to disturbed flow and did not activate the pathways that eventually lead to plaques. “We’re now screening drug libraries to try a drug that blocks only the chair-shaped Plexin D1, so that we can block plaques before they even start,” said Dr Tzima.

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Atherosclerosis, the build-up of fatty plaques inside the arteries, is the underlying cause of devastating heart attacks and strokes. 

“Understanding how and why these plaques develop in particular areas of arteries has been a longstanding challenge for scientists. This groundbreaking study has identified a protein that may be the key sensor that triggers the whole disease process. The very exciting possibility is that new drugs may be developed to target that protein, in order to prevent atherosclerosis developing in the first place - which could ultimately reduce the number of people affected by the world’s biggest killers."

The study was funded by Wellcome Trust, British Heart Foundation, National Institutes of Health and the University of Oxford.

Read the full paper

The main image shows a schematic of the Plexin D1 receptor sticking out of the endothelial layer into the bloodstreatm to sense blood flow. The extracellular, mechanosensing domain is shown in blue. Photo credit: Dr Ellie Tzima.