Oncotarget

Research Papers:

TRPV4 channels regulate tumor angiogenesis via modulation of Rho/Rho kinase pathway

Roslin J. Thoppil, Holly C. Cappelli, Ravi K. Adapala, Anantha K. Kanugula, Sailaja Paruchuri and Charles K. Thodeti _

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Oncotarget. 2016; 7:25849-25861. https://doi.org/10.18632/oncotarget.8405

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Abstract

Roslin J. Thoppil1,2,*, Holly C. Cappelli1,2,*, Ravi K. Adapala1,2, Anantha K. Kanugula1, Sailaja Paruchuri3, Charles K. Thodeti1,2

1Department of Integrative Medical Sciences, Northeast Ohio Medical University, OH 44272, Rootstown, USA

2School of Biomedical Sciences, Kent State University, OH 44240, Kent, USA

3Department of Chemistry, University of Akron, OH 44325, Akron, USA

*These authors contributed equally to this work

Correspondence to:

Charles K. Thodeti, e-mail: [email protected]

Keywords: endothelial cell, mechanotransduction, Rho/Rho kinase, TRPV4, tumor angiogenesis

Received: January 29, 2016     Accepted: March 10, 2016     Published: March 26, 2016

ABSTRACT

Targeting angiogenesis is considered a promising therapy for cancer. Besides curtailing soluble factor mediated tumor angiogenesis, understanding the unexplored regulation of angiogenesis by mechanical cues may lead to the identification of novel therapeutic targets. We have recently shown that expression and activity of mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) is suppressed in tumor endothelial cells and restoring TRPV4 expression or activation induces vascular normalization and improves cancer therapy. However, the molecular mechanism(s) by which TRPV4 modulates angiogenesis are still in their infancy. To explore how TRPV4 regulates angiogenesis, we have employed TRPV4 null endothelial cells (TRPV4KO EC) and TRPV4KO mice. We found that absence of TRPV4 (TRPV4KO EC) resulted in a significant increase in proliferation, migration, and abnormal tube formation in vitro when compared to WT EC. Concomitantly, sprouting angiogenesis ex vivo and vascular growth in vivo was enhanced in TRPV4KO mice. Mechanistically, we observed that loss of TRPV4 leads to a significant increase in basal Rho activity in TRPV4KO EC that corresponded to their aberrant mechanosensitivity on varying stiffness ECM gels. Importantly, pharmacological inhibition of the Rho/Rho kinase pathway by Y-27632 normalized abnormal mechanosensitivity and angiogenesis exhibited by TRPV4KO EC in vitro. Finally, Y-27632 treatment increased pericyte coverage and in conjunction with Cisplatin, significantly reduced tumor growth in TRPV4KO mice. Taken together, these data suggest that TRPV4 regulates angiogenesis endogenously via modulation of EC mechanosensitivity through the Rho/Rho kinase pathway and can serve as a potential therapeutic target for cancer therapy.


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