Everyone develops atherosclerotic plaque that narrows and weakens blood vessel walls in later life. A sizable fraction of all human mortality derives from the consequences of that plaque, such as rupture of unstable plaque to cause a stroke or heart attack. The maladaptive formation of blood clots within or attached to the plaque structure greatly reduces the stability of these structures, and is an important contribution to mortality. Here, researchers show that cells driven into a senescent state by the toxic plaque environment generate the circumstances that provoke inappropriate clot formation in and around an atherosclerotic plaque. Of note, other work has suggested that those same senescent cells may be structurally important to a plaque, and removing them may also cause loss of plaque stability. After a certain point, it becomes hard to resolve the issues a plaque presents. Here, as elsewhere in medicine, prevention is far more desirable than resolution.
Researchers have discovered a molecular pathway that drives certain stressed or aging cells to become abnormally active, causing inflammation inside blood vessel plaques. This results in disturbed blood flow and high-risk lesions that can lead to blood clots that cause heart attacks or strokes. The researchers studied senescent cells, which are stressed or aging cells that have stopped dividing but don’t die. They discovered that losing key regulatory proteins, LATS1 and LATS2, in these cells activates the CD38 enzyme, which reprograms how these cells use energy and makes them more unstable. This leads to inflammation and an increased risk of blood clot formation inside plaques, a process known as atherothrombosis.
The researchers used advanced molecular profiling on preclinical models to show how endothelial cells – the cells lining blood vessels – change with the loss of LATS1/2 proteins, which usually help with healthy cell stabilization. Removing LATS1/2 in endothelial cells caused them to become senescent but also abnormally active. This led to instability, leaky vessels, inflammation, abnormal vessel growth and plaques that could form clots, all of which are pro-thrombotic features.
Further analyses showed that these senescent cells had a dramatic increase in CD38 levels, highlighting their potential role as key drivers of this hybrid state. Preclinical models demonstrated that overexpressing CD38 rewired the metabolic pathways and energy sources for endothelial cells, leading them to consume enough additional energy to drive inflammation. This destabilized plaques and led to the formation of blood clots. Inhibiting CD38 reversed these effects both in vitro and in vivo.
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