Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis.

Title

Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis.

Creator

Cappelli Holly C; Kanugula Anantha K; Adapala Ravi K; Amin Vibhatsu; Sharma Priya; Midha Priya; Paruchuri Sailaja; Thodeti Charles K

Publisher

Cancer letters

Date

2019
2019-02

Description

The transient receptor potential vanilloid 4 (TRPV4) channel is a mechanosensor in endothelial cells (EC) that regulates cyclic strain-induced reorientation and flow-mediated nitric oxide production. We have recently demonstrated that TRPV4 expression is reduced in tumor EC and tumors grown in TRPV4KO mice exhibited enhanced growth and immature leaky vessels. However, the mechanism by which TRPV4 regulates tumor vascular integrity and metastasis is not known. Here, we demonstrate that VE-cadherin expression at the cell-cell contacts is significantly reduced in TRPV4-deficient tumor EC and TRPV4KO EC. In vivo angiogenesis assays with Matrigel of varying stiffness (700-900Pa) revealed a significant stiffness-dependent reduction in VE-cadherin-positive vessels in Matrigel plugs from TRPV4KO mice compared with WT mice, despite an increase in vessel growth. Further, syngeneic Lewis Lung Carcinomatumor experiments demonstrated a significant decrease in VE-cadherin positive vessels in TRPV4KO tumors compared with WT. Functionally, enhanced tumor cell metastasis to the lung was observed in TRPV4KO mice. Our findings demonstrate that TRPV4 channels regulate tumor vessel integrity by maintaining VE-cadherin expression at cell-cell contacts and identifies TRPV4 as a novel target for metastasis.

Subject

Angiogenesis; Mechanotransduction; Stiffness; TRPV4; Vascular integrity; VE-cadherin

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

15–20

Volume

442

Citation

Cappelli Holly C; Kanugula Anantha K; Adapala Ravi K; Amin Vibhatsu; Sharma Priya; Midha Priya; Paruchuri Sailaja; Thodeti Charles K, “Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis.,” NEOMED Bibliography Database, accessed January 23, 2021, https://neomed.omeka.net/items/show/3513.

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