Activation of mechanosensitive ion channel TRPV4 promotes normalization of tumor vasculature and improves cancer therapy (893.12)

The impaired development of tumor vessels, attributed to their highly permeable, tortuous, and hyper-dilatory properties make it a barrier for the efficient delivery of anti-cancer agents. Although anti-VEGF therapies have shown to induce transient normalization of the tumor vasculature and increase the efficacy of cancer drugs, they are met with limited success clinically. Here, we demonstrate that a mechanosenstive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation. Tumor xenograft experiments revealed that, compared to tumors in wild type (WT) mice, those in TRPV4 null mice exhibit greater vascular density and immaturity (increased vessel diameter and reduced pericyte coverage). Endothelial cells derived from the tumor (TEC) showed reduced TRPV4 expression and activity associated with high basal Rho activity as well as aberrant mechanosensitivity and abnormal angiogenesis. Activation of TRPV4 with a small-molecule activator, GSK1016790A, or TRPV4 overexpression suppressed the en...