Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, 44272, USA.
Department of Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Angiogenesis. 2021 Aug;24(3):647-656. doi: 10.1007/s10456-021-09775-9. Epub 2021 Mar 3.
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) mice by crossing TRPV4 mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4 mice compared to TRPV4 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 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.
瞬时受体电位香草醛 4 型（TRPV4）是一种广泛表达的多模式激活的离子通道。TRPV4 被认为与肿瘤进展有关；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 小鼠与 Tie2-Cre 小鼠杂交，产生了内皮细胞特异性 TRPV4 敲除（TRPV4）小鼠。与 TRPV4 小鼠相比，TRPV4 小鼠的同基因 Lewis 肺癌肿瘤模型中的肿瘤生长和转移显著增加。多光子显微镜、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，与异常渗漏血管（增加宽度和减少周细胞和 VE-钙粘蛋白覆盖）相关。在机制上，在 TRPV4 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。我们的结果表明，内皮细胞 TRPV4 是血管完整性和肿瘤血管生成的关键调节剂，而 TRPV4 的缺失促进了肿瘤血管生成、生长和转移。
