TRPV4 mechanosensing contributes to aortic root stiffening and atheroma development

Atherosclerosis is a major contributor to cardiovascular disease, the leading cause of death in developed countries. Emerging evidence suggests that arterial stiffness is a significant risk factor for atherosclerosis, yet the mechanisms driving arterial stiffness and its role in atherogenesis remain poorly understood. Cellular stiffness sensors, such as mechanosensitive channels, may mediate the relationship between matrix stiffening and atherosclerosis. This study explores the role of transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, in regulating aortic stiffness and atherosclerosis. In this study, we investigated the role of TRPV4 in atherosclerosis using ApoE -/- and ApoE -/- TRPV4 -/- mice fed a high-fat diet (HFD) or control chow (both on a C57BL/6 background; n = 10 mice/group). After 12 weeks on HFD, ApoE -/- TRPV4 -/- mice exhibited a 4-fold reduction in atherosclerotic plaque formation in the aortic root and arch compared to ApoE-/- mice. There were no significant differences in body weight gain, plasma total cholesterol (1120 ± 200 vs 1089 ± 170 mg/dL) or triglyceride (120 ± 11 vs 116 ± 12 mg/dL) levels between ApoE -/- Trpv4 -/- and ApoE -/- mice, suggesting that the observed atheroprotective effect may be linked to the absence of TRPV4-dependent functions in this model. Atomic force microscopy (AFM) analysis revealed a 6-fold increase in aortic root stiffness in ApoE-/- mice on HFD, whereas TRPV4-deficient mice showed significantly lower stiffness. These results suggest TRPV4 contributes to aortic stiffening during atherogenesis. Additionally, AFM analysis of macrophages, a critical cell type in atherosclerosis, showed increased stiffness in wild-type macrophages compared to TRPV4 knockout macrophages under both unstimulated and lipopolysaccharide-stimulated conditions. Human aortic root biopsies from atherosclerosis patients showed increased TRPV4, CD68+ macrophages, and α-SMA+ myofibroblasts compared to healthy controls, with a strong correlation between TRPV4 expression and tissue stiffness. Our findings indicate that TRPV4 plays a key role in promoting matrix stiffening and atherosclerosis by regulating the stiffness of both macrophages and aortic tissues. Targeting TRPV4-mediated mechanosensing may offer a novel therapeutic approach to reduce arterial stiffness and slow atherosclerotic progression. This work was supported by an NIH (R01EB024556) grant to Shaik O. Rahaman. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.