title: TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation.
abstract: Endothelial cell proliferation is a critical event during angiogenesis, regulated by both soluble factors and mechanical forces. Although the proliferation of tumor cells is studied extensively, little is known about the proliferation of tumor endothelial cells (TEC) and its contribution to tumor angiogenesis. We have recently shown that reduced expression of the mechanosensitive ion channel TRPV4 in TEC causes aberrant mechanosensitivity that result in abnormal angiogenesis. Here, we show that TEC display increased proliferation compared to normal endothelial cells (NEC). Further, we found that TEC exhibit high basal ERK1/2 phosphorylation and increased expression of proliferative genes important in the G1/S phase of the cell cycle. Importantly, pharmacological activation of TRPV4, with a small molecular activator GSK1016790A (GSK), significantly inhibited TEC proliferation, but had no effect on the proliferation of NEC or the tumor cells (epithelial) themselves. This reduction in TEC proliferation by TRPV4 activation was correlated with a decrease in high basal ERK1/2 phosphorylation. Finally, using a syngeneic tumor model revealed that TRPV4 activation, with GSK, significantly reduced endothelial cell proliferation in vivo. Our findings suggest that TRPV4 channels regulate tumor angiogenesis by selectively inhibiting tumor endothelial cell proliferation.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.|School of Biomedical Sciences, Kent State University, Kent, OH 44240.
authors.forename: Roslin J
authors.initials: RJ
authors.lastname: Thoppil
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.|School of Biomedical Sciences, Kent State University, Kent, OH 44240.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Adapala
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.|School of Biomedical Sciences, Kent State University, Kent, OH 44240.
authors.forename: Holly C
authors.initials: HC
authors.lastname: Cappelli
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325.
authors.forename: Vinay
authors.initials: V
authors.lastname: Kondeti
authors.affiliation: Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Dudley
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.|School of Biomedical Sciences, Kent State University, Kent, OH 44240.
authors.forename: J
authors.initials: J
authors.lastname: Gary Meszaros
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Paruchuri
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.|School of Biomedical Sciences, Kent State University, Kent, OH 44240.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; 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; D007930:Leucine