Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a ubiquitously expressed polymodally activated ion channel. TRPV4 has been implicated in tumor progression; however, the cell-specific role of TRPV4 in tumor growth, angiogenesis, and metastasis is unknown. Here, we generated endothelial-specific TRPV4 knockout (TRPV4ECKO) mice by crossing TRPV4lox/lox mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4ECKO mice compared to TRPV4lox/lox mice. Multiphoton microscopy, dextran leakage, and immunohistochemical analysis revealed increased tumor angiogenesis and metastasis that were correlated with aberrant leaky vessels (increased width and reduced pericyte and VE-cadherin coverage). Mechanistically, increases in VEGFR2, p-ERK, and MMP-9 expression and DQ gelatinase activity were observed in the TRPV4ECKO mouse tumors. Our results demonstrated that endothelial TRPV4 is a critical modulator of vascular integrity and tumor angiogenesis and that deletion of TRPV4 promotes tumor angiogenesis, growth, and metastasis.
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The data to support the findings of the present study are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by the National Institutes of Health [NIH-(R15CA202847; R01HL119705 and R01HL148585 to CKT; R01 AI144115 and R15HL133918 to SP].
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AK, RA, AJ, NL and BG performed the research, analyzed the data, and edited the manuscript. WL provided the TRPV4lox/lox mice and edited the manuscript. LY and SP edited the manuscript. CKT designed, interpreted, and analyzed the data and wrote the manuscript.
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Kanugula, A.K., Adapala, R.K., Jamaiyar, A. et al. Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity. Angiogenesis 24, 647–656 (2021). https://doi.org/10.1007/s10456-021-09775-9
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DOI: https://doi.org/10.1007/s10456-021-09775-9