Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells

• Published in: Advanced science 2024-03, Vol.11 (9), p.e2308686-n/a
• Main Authors: Swiatlowska, Pamela, Tipping, William, Marhuenda, Emilie, Severi, Paolo, Fomin, Vitalay, Yang, Zhisheng, Xiao, Qingzhong, Graham, Duncan, Shanahan, Cathy, Iskratsch, Thomas
• Format: Article
• Language: English
• Subjects: atherosclerosis; foam cells; mechanosensing; pressure sensing; vascular smooth muscle cells
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202308686

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 >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. Hypertensive pressure dependent vascular smooth muscle cells foam cell formation. Pressure leads to opening of Piezo1 channels at the outer, or inner nuclear membrane (ONM, INM). Calcium recruits cPLA2 to the INM, where it leads to cleavage of arachidonic acid (AA) and lipid droplet formation. Downstream of AA processing, reactive oxygen species (ROS) lead to epigenetic changes.