Endothelial cells that line the inside of arteries often reshape themselves as the flow of blood changes. Sometimes, such responses lead to cardiovascular problems.
A research team led by the University of Oxford has discovered a molecular “first responder” that detects blood-flow stress. Targeting the shape of this force detector holds promise for preventing serious heart diseases, they argue.
Plexin D1, a member of the key cell-surface receptor family Plexin, acts as a “mechanosensor” in endothelial cells. It can respond to the dynamic forces of blood flow by promoting the formation of plaques that clog up the arteries, leading to atherosclerosis, the usual cause of heart attacks and stroke, the team described in a study published in Nature.
Scientists have known for a long time that plaques are much more likely to form where arteries curve or split. But it was unclear what the exact molecular features were behind the cascade of inflammation that leads to the buildup of plaques in the arteries.
“The blood flowing through our arteries is like a river,” Ellie Tzima, the study’s senior author, said in a statement. “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.”
Tzima and colleagues first set off to determine the role of Plexin D1 in the response to blood-flow disturbance. In bovine endothelial cells, knocking down Plexin D1 reduced the activation of key signaling pathways related to the flow conditions. In mouse cells, the procedure significantly cut back the upregulation of pro-inflammatory genes. This suggests that the protein is a critical mediator of endothelial cells’ reaction to blood flow, the researchers said in the study.
To assess whether the decrease in the expression of inflammatory genes they observed in lab dishes was meaningful, the scientists deleted Plexin D1 in mice and fed them with an unhealthy high-fat diet for 10 weeks. The animals didn’t develop plaques in their arteries.
“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,” Tzima explained.
Interestingly, small populations of more-open, chair-shaped Plexin D1 responded to the magnetic tweezer pull, while their ring-shaped counterparts didn’t. The researchers genetically engineered cells to only express ring-shaped Plexin D1. These mutant cells didn’t respond to mechanical force and were unable to activate several pathways that could lead to plaques, they found.
Other scientific groups have also targeted mechanosensors to help prevent blood vessels from being blocked. Scientists at the Scripps Research Institute previously identified the protein GRP68 as a key blood flow detector, which could prompt blood vessels to dilate.
Investors are also pouring funding into companies developing novel therapies for heart disease. For example, Tenaya Therapeutics recently raised $92 million in its series B round to help it develop regenerative treatments, gene therapies and precision medicines for heart disease.
The Oxford University researchers hope their discovery of Plexin D1 will translate into drugs that can lower the risk of cardiovascular disorders caused by blood clots. “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,” Tzima said.