Related Experiment Video
Updated: Apr 3, 2026
Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
Published on: December 31, 2013
TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation
Roslin J Thoppil1,2, Ravi K Adapala1,2, Holly C Cappelli1,2
1Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272.
Abstract:
Endothelial cell proliferation is a critical event during angiogenesis, regulated by both soluble factors and mechanical forces. Although the proliferation of tumor cells is studied extensively, little is known about the proliferation of tumor endothelial cells (TEC) and its contribution to tumor angiogenesis. We have recently shown that reduced expression of the mechanosensitive ion channel TRPV4 in TEC causes aberrant mechanosensitivity that result in abnormal angiogenesis. Here, we show that TEC display increased proliferation compared to normal endothelial cells (NEC). Further, we found that TEC exhibit high basal ERK1/2 phosphorylation and increased expression of proliferative genes important in the G1/S phase of the cell cycle. Importantly, pharmacological activation of TRPV4, with a small molecular activator GSK1016790A (GSK), significantly inhibited TEC proliferation, but had no effect on the proliferation of NEC or the tumor cells (epithelial) themselves. This reduction in TEC proliferation by TRPV4 activation was correlated with a decrease in high basal ERK1/2 phosphorylation. Finally, using a syngeneic tumor model revealed that TRPV4 activation, with GSK, significantly reduced endothelial cell proliferation in vivo. Our findings suggest that TRPV4 channels regulate tumor angiogenesis by selectively inhibiting tumor endothelial cell proliferation.
Insights
Activating the TRPV4 channel selectively inhibits tumor endothelial cell proliferation by reducing ERK1/2 phosphorylation. This finding offers a new therapeutic target for regulating tumor angiogenesis.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Endothelial cell proliferation is crucial for angiogenesis, yet tumor endothelial cell (TEC) proliferation remains understudied.
- Reduced TRPV4 expression in TEC leads to abnormal angiogenesis due to altered mechanosensitivity.
Purpose of the Study:
- To investigate the role of TRPV4 in regulating TEC proliferation and its contribution to tumor angiogenesis.
- To determine if pharmacological activation of TRPV4 can inhibit TEC proliferation.
Main Methods:
- Comparison of proliferation rates between TEC and normal endothelial cells (NEC).
- Analysis of ERK1/2 phosphorylation and cell cycle gene expression in TEC.
- Pharmacological activation of TRPV4 using GSK1016790A (GSK) in vitro and in a syngeneic tumor model.
- Assessment of GSK's effect on TEC, NEC, and tumor cell proliferation in vivo.
Main Results:
- TEC exhibit higher proliferation rates than NEC, with elevated basal ERK1/2 phosphorylation and increased expression of G1/S phase genes.
- GSK-mediated TRPV4 activation significantly inhibited TEC proliferation, correlating with decreased ERK1/2 phosphorylation.
- GSK did not affect NEC or tumor cell proliferation.
- In vivo studies confirmed that GSK significantly reduced endothelial cell proliferation within tumors.
Conclusions:
- TRPV4 channels play a critical role in regulating tumor endothelial cell proliferation.
- Pharmacological activation of TRPV4 presents a potential strategy to inhibit tumor angiogenesis by selectively targeting TEC proliferation.
More Related Videos
09:42Assessing Tumor Microenvironment of Metastasis Doorway-Mediated Vascular Permeability Associated with Cancer Cell Dissemination using Intravital Imaging and Fixed Tissue Analysis
Published on: June 26, 2019
08:46Strategic Endothelial Cell Tube Formation Assay: Comparing Extracellular Matrix and Growth Factor Reduced Extracellular Matrix
Published on: August 14, 2016
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
02:17The Tumor Microenvironment
02:17The Tumor Microenvironment
01:27Tumor Immunotherapy
02:07Tumor Progression
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...