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Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4
Author(s) -
Kanugula Anantha K.,
Adapala Ravi K.,
Midha Priya,
Cappelli Holly C.,
Meszaros J. Gary,
Paruchuri Sailaja,
Chilian William M.,
Thodeti Charles K.
Publication year - 2019
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/fj.201800509r
Subject(s) - mechanosensitive channels , trpv4 , angiogenesis , microbiology and biotechnology , gene knockdown , signal transduction , chemistry , small interfering rna , phosphorylation , kinase insert domain receptor , transient receptor potential channel , biology , vascular endothelial growth factor , ion channel , vascular endothelial growth factor a , receptor , transfection , cancer research , biochemistry , vegf receptors , gene , apoptosis
VEGF signaling via VEGF receptor‐2 (VEGFR2) is a major regulator of endothelial cell (EC) functions, including angiogenesis. Although most studies of angiogenesis focus on soluble VEGF signaling, mechanical signaling also plays a critical role. Here, we examined the consequence of disruption of mechanical signaling on soluble signaling pathways. Specifically, we observed that small interfering RNA (siRNA) knockdown of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), significantly reduced perinuclear (Golgi) VEGFR2 in human ECs with a concomitant increase in phosphorylation at Y1175 and membrane translocation. TRPV4 knockout (KO) ECs exhibited increased plasma membrane localization of phospho‐VEGFR2 compared with normal ECs. The knockdown also increased phospho‐VEGFR2 in whole cell lysates and membrane fractions compared with control siRNA‐treated cells. siRNA knockdown of TRPV4 enhanced nuclear localization of mechanosensitive transcription factors, yes‐associated protein/transcriptional coactivator with PDZ‐binding motif via rho kinase, which were shown to increase VEGFR2 trafficking to the plasma membrane. Furthermore, TRPV4 deletion/knockdown enhanced VEGF‐mediated migration in vitro and increased expression of VEGFR2 in vivo in the vasculature of TRPV4 KO tumors compared with wild‐type tumors. Our results thus show that TRPV4 channels regulate VEGFR2 trafficking and activation to identify novel cross‐talk between mechanical (TRPV4) and soluble (VEGF) signaling that controls EC migration and angiogenesis.—Kanugula, A. K., Adapala, R. K., Midha, P., Cappelli, H. C., Meszaros, J. G., Paruchuri, S., Chilian, W. M., Thodeti, C. K., Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4. FASEB J. 33, 195–203 (2019). www.fasebj.org