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

Roslin J Thoppil1,2, Holly C Cappelli1,2, Ravi K Adapala1,2

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

Oncotarget
|March 31, 2016
PubMed

Insights

Restoring the mechanosensitive ion channel TRPV4 normalizes tumor blood vessels by regulating Rho activity. This finding reveals TRPV4 as a potential therapeutic target for improving cancer treatment outcomes.

Area of Science:

  • Oncology
  • Vascular Biology
  • Mechanobiology

Background:

  • Targeting tumor angiogenesis is a key cancer therapy strategy.
  • Mechanical cues, alongside soluble factors, regulate angiogenesis.
  • The mechanosensitive ion channel TRPV4 is suppressed in tumor endothelial cells, and its restoration improves cancer therapy.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TRPV4 (transient receptor potential vanilloid 4) modulates angiogenesis.
  • To investigate the role of TRPV4 in endothelial cell mechanosensitivity and its impact on angiogenesis.
  • To evaluate TRPV4 as a potential therapeutic target in cancer treatment.

Main Methods:

  • Utilized TRPV4 null endothelial cells (TRPV4KO EC) and TRPV4KO mice.
  • Assessed endothelial cell proliferation, migration, and tube formation in vitro.
  • Measured ex vivo sprouting angiogenesis and in vivo vascular growth.
  • Investigated Rho activity and mechanosensitivity on varying extracellular matrix (ECM) stiffness.
  • Employed pharmacological inhibition of the Rho/Rho kinase pathway using Y-27632.

Main Results:

  • TRPV4 deficiency (TRPV4KO EC) significantly increased endothelial cell proliferation, migration, and abnormal tube formation in vitro.
  • Sprouting angiogenesis ex vivo and vascular growth in vivo were enhanced in TRPV4KO mice.
  • Loss of TRPV4 led to increased basal Rho activity and aberrant mechanosensitivity in TRPV4KO EC.
  • Pharmacological inhibition of Rho/Rho kinase pathway normalized mechanosensitivity and angiogenesis in TRPV4KO EC.
  • Y-27632 treatment improved pericyte coverage and, with Cisplatin, reduced tumor growth in TRPV4KO mice.

Conclusions:

  • TRPV4 regulates angiogenesis by modulating endothelial cell mechanosensitivity via the Rho/Rho kinase pathway.
  • Restoring TRPV4 function normalizes aberrant angiogenesis associated with cancer.
  • TRPV4 represents a promising therapeutic target for enhancing cancer therapy by normalizing tumor vasculature.
Keywords:
Rho/Rho kinaseTRPV4endothelial cellmechanotransductiontumor angiogenesis

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