Hypertension Pressure Turns Vascular Smooth Muscle Cells into Foam Cells
The raised blood pressure of hypertension correlates with the development of atherosclerosis, a condition characterized by cholesterol-rich lesions that grow in blood vessel walls. Researchers have proposed mechanisms by which hypertension can cause cell dysfunction, such as by indirectly increasing circulating immune cell numbers, cells that are then drawn into the plaque and killed by it, increasing its mass. More directly, increased pressure on arterial walls causes them to become less permeable to cholesterol carried in the bloodstream, encouraging deposits to form in the inner blood vessel wall. As another potential mechanism, researchers here identify a way in which increased pressure can induced pathological dysfunction in the vascular smooth muscle cells that become involved in atherosclerosis.
Arterial vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up more than 50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear.
Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways.
Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.