Shapeshifting muscle cells – the good and bad guy in atherosclerosis

Around 18 million people die from cardiovascular disease each year, making it the leading cause of death worldwide. The main cause of cardiovascular disease is atherosclerosis, a process that occurs when fatty substances, cholesterol, and cell debris accumulate in blood vessel walls and form so-called “atherosclerotic plaques”. The progressive development of atherosclerosis is complex, as it involves genetic predispositions as well as environmental factors, such as an unhealthy diet, physical inactivity and smoking. Over time, atherosclerotic plaques can become unstable and prone to rupture. Plaque rupture leads to the formation of a blot clot or “thrombus”, which can occlude a blood vessel and thereby cause a heart attack or stroke.

Various cell types in the blood vessel wall contribute to the initiation and progression of atherosclerosis, including smooth muscle cells (a type of muscle cell found in the walls of hollow organs), endothelial cells (that line the inner surface of blood vessels), and macrophages (a large immune cell found in tissues at sites of infection or tissue damage). Remarkably, smooth muscle cells can change the way they look and function depending on the tissue microenvironment, a process referred to as “phenotypic switching”. Dr. Huize Pan, a postdoc from Columbia University, investigated this phenomenon in the context of atherosclerosis, to find out whether smooth muscle cells are the good or bad guy in this disease. As it turns out, they are both.

Smooth muscle cells can transition to fibrotic cells that synthesize a fibrous cap covering the atherosclerotic plaque. This is a beneficial process as it reduces the likelihood of plaque rupture. However, in their recent paper published in Circulation, Dr. Pan and colleagues show that smooth muscle cells can also turn into intermediate stem cell-like cells that can further differentiate into macrophage-like cells (see Figure below). This “shapeshifting” of smooth muscle cells towards macrophage-like cells could be harmful as certain macrophages are known to promote plaque inflammation and instability.

Depending on the state of retinoic acid signaling, smooth muscle cells can either turn into fibrotic cells and play a protective role in atherosclerosis, or turn into intermediate stem-cell like cells that give rise to inflammatory macrophage-like cells, thereby increasing plaque instability and the risk of heart disease. Figure adapted from Pan, Circ 2020, and created with

This raises the question of how smooth muscle cells either become more fibrotic and play a protective role in atherosclerosis or transdifferentiate into inflammatory macrophage-like cells and play a damaging role. Through single-cell RNA sequencing analysis, a research method to examine which genes are turned “on” and “off” in individual cells, Dr. Pan and colleagues found significant differences in target genes of retinoic acid signaling between smooth muscle cells and intermediate stem cell-like cells. This indicates that signaling through retinoic acid, a derivative of vitamin A that helps regulate growth and development, could be an important mechanism by which smooth muscle cells transition to other cell states (as depicted in the Figure above).

Next, the researchers explored whether these findings are relevant for human heart disease. Indeed, they found dysregulated retinoic acid signaling in human atherosclerotic plaques, and discovered that human individuals with genetic variation in target genes of retinoic acid signaling have a higher risk of cardiovascular disease. These findings suggest that by determining smooth muscle cell fate, retinoic acid signaling controls the outcome of atherosclerotic cardiovascular disease. Manipulation of retinoic acid signaling could therefore be a promising therapeutic strategy to reduce cardiovascular risk. This is supported by the current study, through the use of an FDA-approved drug named ATRA (activation of RA signaling by all-trans RA) that activates retinoic acid signaling. ATRA reduced the number of smooth muscle cell-derived macrophages, reduced atherosclerosis progression, and increased fibrous cap thickness in a mouse model of atherosclerosis.

Taken together, these novel findings indicate that smooth muscle cells can play both the good and bad guy in atherosclerosis. By promoting smooth muscle cells in atherosclerotic plaques to follow the “righteous path”, we are one step closer to a world free of heart disease.

Leave a Reply

Your email address will not be published.

Follow this blog

Get every new post delivered right to your inbox.