Background: Atherosclerosis, the leading cause of cardiovascular disease, is driven by the formation of unstable lesions in large arteries. Endothelial-to-mesenchymal transition (EndMT) plays a critical role in the progression of atherosclerotic lesions. However, endothelial mechanisms underlying EndMT and lesion development remain unclear. Transient Receptor Potential Vanilloid 4 (TRPV4), a Ca 2 + -permeable cation channel, has beneficial effects on endothelial health in small arteries under normal conditions. However, the role of endothelial TRPV4 channels in the development of atherosclerotic lesions is unknown. Hypothesis: Endothelial TRPV4 channels limit EndMT and the development of atherosclerotic lesions. Methods: We generated tamoxifen-inducible, EC eYFP-lineage-tracing, EC-specific TRPV4 knockout Apoe−/− mice (Cdh5-CreERT2; Trpv4Flox/Flox; Rosa-Stop-eYFP+/+Apoe−/− or TRPV4ECKO) and control littermates (Cdh5-CreERT2; Trpv4WT/WT; Rosa-Stop-eYFP+/+Apoe−/− or TRPV4WT). Mice were fed a Western diet for 18 weeks to induce the development of advanced lesions. Plaque size, lesion stability, and EndMT were assessed using histological and immunofluorescence analyses, as well as single-cell RNA sequencing (sc-RNAseq), in the brachiocephalic artery (BCA). Results: 1. Morphometric analysis showed that EC-specific TRPV4 deletion significantly increased lesion size and EndMT compared to controls but did not alter collagen content, an index of lesion stability. 2. sc-RNAseq analysis of ECs (eYFP-positive cells) from the lesions showed that a loss of endothelial TRPV4 increased EndMT and transforming growth factor b (TGFb) signaling, which drives EndMT. 3. Pharmacological inhibition of TRPV4 channels also increased lesion size and reduced lesion collagen content. Conclusion: Taken together, our data indicate that endothelial TRPV4 channels limit progression of atherosclerotic lesions in BCA, likely by suppressing TGFb-driven EndMT. This abstract was presented at the American Physiology Summit 2026 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.
Kuppusamy et al. (Fri,) studied this question.