title: Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
abstract: Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: R K
authors: RK
authors: Adapala
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: R J
authors: RJ
authors: Thoppil
authors: Department of Bioengineering, University of California, Riverside, CA, USA.|Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors: K
authors: K
authors: Ghosh
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: H C
authors: HC
authors: Cappelli
authors: Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA, USA.|Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC, USA.
authors: A C
authors: AC
authors: Dudley
authors: Department of Chemistry, University of Akron, Akron, OH, USA.
authors: S
authors: S
authors: Paruchuri
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors: V
authors: V
authors: Keshamouni
authors: Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors: M
authors: M
authors: Klagsbrun
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: J G
authors: JG
authors: Meszaros
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: W M
authors: WM
authors: Chilian
authors: Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA, USA.|Wyss Institute for Biologically Inspired Engineering and Harvard School of Engineering and Applied Sciences, Cambridge, MA, USA.
authors: D E
authors: DE
authors: Ingber
authors: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.|Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors: C K
authors: CK
authors: Thodeti
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage; D050916:TRPV Cation Channels / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D007930:Leucine; D002945:Cisplatin