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TRPV4 Channels Regulate Tumor Angiogenesis via Modulation of ERK1/2‐Dependent Tumor Endothelial Cell Proliferation
Author(s) -
Thoppil Roslin,
Adapala Ravi,
Cappelli Holly,
Paruchuri Sailaja,
Meszaros J Gary,
Thodeti Charles
Publication year - 2015
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.29.1_supplement.796.5
Subject(s) - angiogenesis , tec , cell growth , cancer research , microbiology and biotechnology , chemistry , trpv4 , neovascularization , biology , biochemistry , receptor , ion channel , ionosphere , physics , astronomy
The proliferation of endothelial cells (EC) is a critical event in angiogenesis, regulated by both soluble factors and mechanical forces. Although unregulated proliferation of tumor cells is well known, very little is understood about Tumor EC (TEC) proliferation and their role in tumor angiogenesis. We have recently found that TEC express low functional levels of the mechanosensitive ion channel TRPV4 which imparts aberrant mechanosensitivity leading to abnormal angiogenesis by TEC. Here, we investigated if TRPV4 plays a role in TEC proliferation and tumor angiogenesis. First, we found tumors implanted in TRPV4 ‐/‐ mice exhibited enhanced angiogenesis and increased growth compared to wild‐type (WT) tumors. Next, aortic ring explants from TRPV4 ‐/‐ mice displayed significantly increased angiogenesis compared to the WT controls. In vitro studies showed TEC (and TRPV4‐null ECs) proliferated at higher levels than NEC. Subsequently, we found TEC and TRPV4 ‐/‐ EC to have high basal ERK1/2 activity compared to their normal counterparts. Importantly, either TRPV4 overexpression or TRPV4 activation with a small molecule activator, GSK1016790A, significantly inhibited elevated basal ERK1/2 phosphorylation levels and cell proliferation in TEC. Interestingly, TRPV4 activation also inhibited the increased expression of cell cycle associated genes, responsible for cell proliferation. Finally, we found that EC proliferation is higher in WT tumors which was significantly inhibited by GSK1016790A. Taken together, these findings suggest TRPV4 regulates tumor angiogenesis via modulation of ERK1/2‐dependent TEC proliferation.