Over the last few years researchers have gathered data that suggests smooth muscle cells have a more important role in the later stages of atherosclerosis than previously suspected. This new result adds to the evidence:
Until now, doctors have believed that smooth muscle cells - the cells that help blood vessels contract and dilate - were the good guys in the body's battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells in that wall -- particularly in the innermost layer referred to as the "fibrous cap" -- the more stable the plaque is and the less danger it poses.
Recent research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself. "We suspected there was a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods. It wasn't a small number. It was 82 percent. Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion."
The problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It's very confusing and it has led to "complete ambiguity as to which cell is which within the lesion." (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)
Researchers identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when Klf4 was selectively knocked out in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable - the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions but resulted in them undergoing transitions in their functional properties that appear to be beneficial.