Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity

• Published in: Angiogenesis (London) Vol. 24; no. 3; pp. 647 - 656
• Main Authors: Kanugula, Anantha K., Adapala, Ravi K., Jamaiyar, Anurag, Lenkey, Nina, Guarino, Brianna D., Liedtke, Wolfgang, Yin, Liya, Paruchuri, Sailaja, Thodeti, Charles K.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2021; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Cadherins; Cancer Research; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Cardiology; Cell Biology; Dextran; Dextrans; Gelatinase; Gelatinase B; Gene Expression Regulation, Neoplastic; Integrity; Ion channels; Liquid oxygen; Lung cancer; Lung carcinoma; Metastases; Metastasis; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Ophthalmology; Original Paper; Transient receptor potential proteins; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Tumors; Tumor angiogenesis; Endothelial cell; Metastasis; Transient receptor potential vanilloid 4; Vascular endothelial growth factor receptor 2
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-021-09775-9

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 (TRPV4 ECKO ) mice by crossing TRPV4 lox/lox  mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4 ECKO mice compared to TRPV4 l ox/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 TRPV4 ECKO  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.