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

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

doi:10.18632/oncotarget.8405

Roslin J Thoppil, Ravi K Adapala + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.8405

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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.

Highlights

A key hallmark in the growth and progression of solid tumors is the sustained stimulation of angiogenesis [1]
We found that TRPV4KO endothelial cell (EC) showed increased proliferation (Figure 1A)
We found that this increased proliferation correlated with enhanced ERK1/2 phosphorylation in TRPV4KO EC (Figure 1B)

Summary

Introduction

A key hallmark in the growth and progression of solid tumors is the sustained stimulation of angiogenesis [1]. Tumor angiogenesis is an important control point for the progression of any solid tumor the resulting vasculature is highly abnormal, making the delivery of anti-cancer therapies difficult [4]. These challenges led to the development of anti-angiogenic therapies, which aim to target tumor angiogenesis as opposed to solely suppressing tumor growth. Many of these studies have focused on pro-angiogenic signaling pathways but have been met with limited success due to acquired resistance and/or impaired drug delivery, as well as their adverse effects on normal tissue [5,6]. The identification of alternative therapies that target tumor angiogenesis are still of high value

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