Atherosclerosis involves the development of lipid deposits, called plaques, in blood vessel walls. Plaques narrow and weaken those vessels, ultimately producing the inevitable structural failure of a stroke or heart attack. Perhaps a sixth of humanity dies because of atherosclerosis, but means to treat the condition are so far only capable of somewhat slowing it down, with little reversal of existing plaque. Most approaches, such as statin drugs, focus on reducing the level of lipids in circulation in the bloodstream.
Why does a reduction of blood lipids work to slow atherosclerosis? Atherosclerosis is a condition of dysfunctional macrophages. The immune cells called macrophages are responsible for clearing lipid deposits from blood vessel walls. Where cells become disturbed by the presence of lipids, they secrete inflammatory signals calling for assistance. Macrophages arrive and set to work to ingest the lipids and hand them off to HDL particles in the bloodstream that can carry lipids to the liver for excretion. This all works quite well in youth. But with age, an ever greater fraction of lipids become oxidized in ways that macrophages cannot cope with. Macrophages become distressed, inflammatory, and die, adding their debris to a growing plaque. Their inflammatory signals attract ever more macrophages, in a feedback loop that accelerates the condition. When blood lipids are globally reduced, so are the problem oxidized lipids to the same degree, putting that much less stress on macrophage populations. But it is far from enough to cure the condition.
In the research noted here, scientists target TGF-β, an important signaling molecule. Of note, a sizable fraction of distressed macrophages are in fact senescent cells. Cellular senescence is an inflammatory state that cells adopt in response to damage or stress, and senescent cells secrete signals that encourage other cells to become senescent as well. TGF-β is prominently involved in the signaling produced by senescent cells, and it is plausible that sabotaging it can help to take some of the pressure off in the stressed environment of plaque-ridden blood vessel walls, in much the same way as reducing the input of oxidized lipids can take some of the pressure off. The degree to which it will be effective is something of an open question until tried in humans, however, as past lines of research into therapies for atherosclerosis have typically demonstrated quite poor correlations in reversal of plaque buildup between mouse models and humans.
Current treatments for plaque and hardened arteries, a condition known as atherosclerosis, can slow but not improve the disease. Experts believe that may be due to ongoing inflammation in blood vessels. To understand the factors contributing to this inflammation, the research team focused on a group of proteins, called transforming growth factor beta (TGFß), that regulates a wide range of cells and tissues throughout the body.
Using cultured human cells, the researchers discovered that TGFβ proteins trigger inflammation in endothelial cells - the cells that form the inner lining of artery walls - but not in other cell types. With a technique called single cell RNA-seq analysis, which measures the expression of every gene in single cells, they then showed that TGFβ induced inflammation in these cells in mouse models. This finding was notable because TGFβ proteins are known to decrease inflammation in other cells in the body. The researchers also showed that when the TGFβ receptor gene is deleted in endothelial cells, both the inflammation and plaque in blood vessels are significantly reduced.
To test this approach as a potential therapy, the team used RNAi to disrupt TGFß receptors. To deliver the drug only to endothelial cells in the blood vessel walls of mice, they employed nanoparticles. This strategy reduced inflammation and plaque as effectively as the genetic technique. The findings identify TGFß signaling as a major cause of chronic vessel wall inflammation, and demonstrate that disruption of this pathway leads to cessation of inflammation and substantial regression of existing plaque.
Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined.
Here we show that endothelial transforming growh factor β (TGF-β) signalling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGF-β signalling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These proinflammatory effects of endothelial TGF-β signalling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type-specific therapeutic intervention aimed at control of this disease.