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^lox/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.

瞬时受体电位香草酸 4 (TRPV4) 是一种普遍表达的多模式激活离子通道。TRPV4 与肿瘤进展有关；然而，TRPV4 在肿瘤生长、血管生成和转移中的细胞特异性作用尚不清楚。^{在这里，我们通过将 TRPV4 lox/lox} 小鼠与 Tie2-Cre 小鼠杂交，产生了内皮特异性 TRPV4 敲除 (TRPV4 ^{ECKO ) 小鼠。与 TRPV4 l ox/lox}相比， TRPV4 ^ECKO小鼠的同基因 Lewis 肺癌肿瘤模型中的肿瘤生长和转移显着增加老鼠。多光子显微镜检查、葡聚糖渗漏和免疫组织化学分析显示肿瘤血管生成和转移增加，这与异常渗漏血管（宽度增加和周细胞和 VE-钙粘蛋白覆盖率降低）相关。^{在机制上，在 TRPV4 ECKO} 小鼠肿瘤中观察到 VEGFR2、p-ERK 和 MMP-9 表达和 DQ 明胶酶活性的增加。我们的研究结果表明，内皮 TRPV4 是血管完整性和肿瘤血管生成的关键调节剂，TRPV4 的缺失促进了肿瘤血管生成、生长和转移。