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TRPV4 Channel Activation Inhibits Tumor Endothelial Cell Proliferation and Migration Via Modulation of ERK1/2 pathway
Author(s) -
Thoppil Roslin,
Adapala Ravi K,
Cotman Steven,
Paruchuri Sailaja,
Chilian William M,
Meszaros J.Gary,
Thodeti Charles K
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.685.11
Subject(s) - tec , angiogenesis , trpv4 , microbiology and biotechnology , chemistry , cell growth , mechanosensitive channels , cancer research , biology , ion channel , biochemistry , receptor , ionosphere , physics , astronomy
We have previously shown that endothelial cells derived from tumor (TEC) exhibit aberrant Rho‐mediated mechanosensitivity that may be the underlying cause for abnormal tumor vessel formation. We recently found that TEC demonstrate significantly diminished expression and activity of a mechanosensitive ion channel, TRPV4, and exhibit abnormal angiogenesis compared to normal endothelial cells (NEC). Since angiogenesis involves endothelial cell proliferation and migration, in the present study, we investigated if activation of TRPV4 influences TEC proliferation and migration. We demonstrate higher basal proliferation and migration in TEC compared to NEC. Interestingly, activation of TRPV4 by a specific TRPV4 agonist, GSK101690A, significantly inhibited TEC proliferation. We found that basal ERK1/2 activity was higher in TEC when compared to NEC, which was significantly down regulated by GSK101690A. We further found that GSK101690A treatment inhibited abnormal TEC migration. Finally, we demonstrate that TRPV4 activation/overexpression normalized abnormal angiogenesis exhibited by TEC in 2D and 3D angiogenesis assays. Taken together, our results suggest that activation of TRPV4 normalizes angiogenesis by inhibiting abnormal proliferation and migration of TEC via modulation of ERK1/2 activity and proposes that TRPV4 is a novel target for vascular normalization therapies.