Mechanosensitive ion channel TRPV4 modulates endothelial autophagy and angiogenesis through the YAP/AMPK/mTOR pathway

Autophagy is a physiological process responsible for degrading misfolded proteins and damaged organelles within cells. However, the role of endothelial autophagy in angiogenesis remains poorly understood. In this study, we demonstrate that knockdown of TRPV4 channels attenuated autophagy in human endothelial cells (EC) in a matrix stiffness-dependent manner as evidenced by reduced LC3B-II positive autophagosomes. Unbiased RNA sequencing further revealed decreased expression of autophagy genes in TRPV4 knocked down EC compared to WT EC. Mechanistically, TRPV4 knockdown led to increased nuclear translocation of YAP and reduced LC3B-II expression. Notably, the inhibition of YAP with verteporfin restored LC3B-II autophagosomes in TRPV4 knocked down EC. Interestingly, TRPV4 knockdown resulted in significant downregulation of phospho-AMPK and concomitant upregulation of phospho-mTOR. Treatment with rapamycin reversed AMPK/MTOR expression pattern and normalized abnormal angiogenesis exhibited by TRPV4 knocked down EC. Finally, in a pathological tumor angiogenesis model, verteporfin-mediated YAP inhibition significantly reduced tumor angiogenesis and tumor growth in TRPV4 -/- mice compared to TRPV4 +/+ mice. These findings suggest that TRPV4 regulates endothelial autophagy via YAP/AMPK/mTOR pathway during angiogenesis and identifies TRPV4 as a potential therapeutic target for tumor angiogenesis and growth. This work was supported by the National Institutes of Health and American Heart Association (R01HL148585 and AHA-TPA-971237) to CKT. 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.