TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling
Open accessAbstract
Changes in intracellular calcium [Ca(2+)](i) levels control critical cytosolic and nuclear events that are involved in the initiation and progression of tumor angiogenesis in endothelial cells (ECs). Therefore, the mechanism(s) involved in agonist-induced Ca(2+)(i) signaling is a potentially important molecular target for controlling angiogenesis and tumor growth. Several studies have shown that blood vessels in tumors differ from normal vessels in their morphology, blood flow and permeability. We had previously reported a key role for arachidonic acid (AA)-mediated Ca(2+) entry in the initial stages of tumor angiogenesis in vitro. In this study we assessed the mechanism involved in AA-induced EC migration. We report that TRPV4, an AA-activated channel, is differentially expressed in EC derived from human breast carcinomas (BTEC) as compared with 'normal' EC (HMVEC). BTEC display a significant increase in TRPV4 expression, which was correlated with greater Ca(2+) entry, induced by AA or 4αPDD (a selective TRPV4 agonist) in the tumor-derived ECs. Wound-healing assays revealed a key role of TRPV4 in regulating cell migration of BTEC but not HMVEC. Knockdown of TRPV4 expression completely abolished AA-induced BTEC migration, suggesting that TRPV4 mediates the pro-angiogenic effects promoted by AA. Furthermore, pre-incubation of BTEC with AA induced actin remodeling and a subsequent increase in the surface expression of TRPV4. This was consistent with the increased plasma membrane localization of TRPV4 and higher AA-stimulated Ca(2+) entry in the migrating cells. Together, the data presented herein demonstrate that: (1) TRPV4 is differentially expressed in tumor-derived versus 'normal' EC; (2) TRPV4 has a critical role in the migration of tumor-derived but not 'normal' EC migration; and (3) AA induces actin remodeling in BTEC, resulting in a corresponding increase of TRPV4 expression in the plasma membrane. We suggest that the latter is critical for migration of EC and thus in promoting angiogenesis and tumor growth.
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The F-actin rearrangement is most likely through Ca2+-dependent processes.
“most likely through Ca 2+ -dependent processes, 35”
From Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model (2019) · cites this paper as [35]
The Results section on AA-induced Ca2+ responses places actin remodeling upstream of the TRPV4-mediated Ca2+ response, rather than describing F-actin rearrangement as Ca2+-dependent. The Results section on actin remodeling also reports that activating TRPV4 with 4αPDD does not affect actin. Our copy provides no page numbers for these passages. (LLM, conf=0.78)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredHUVECs may not entirely recapitulate all known roles for TRPV4 in tumor vasculature.
“HUVECs may not entirely recapitulate all known roles for TRPV4 in tumor vasculature. 24,28,35,51,53,66”
From Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model (2019) · cites this paper as [35]
The Results section reports higher TRPV4 expression and responses in tumor-derived endothelial cells than in the normal microvascular endothelial cells tested, supporting the caution that a normal-cell model may not capture tumor-vascular TRPV4 biology. The paper does not directly compare HUVECs with tumor-derived endothelial cells, so the HUVEC-specific part remains untested (page not provided in our copy). (LLM, conf=0.82)
Experimental — accuracy not yet measuredTRPV4 expression levels are higher in tumor-associated ECs (TECs) relative to normal ECs.
“Evidence suggests TRPV4 expression levels are higher in tumor-associated ECs (TECs) relative to normal ECs 35”
From Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model (2019) · cites this paper as [35]
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- Authors
- Fiorio Pla, A., Ong, H. L., Cheng, K. T., Brossa, A., Bussolati, B., Lockwich, T., Paria, B., Munaron, L., & Ambudkar, I. S.
- Affiliations
- National Institutes of Health (US)
- University of Turin (IT)
- Venue
- Oncogene
- Published
- 2011-06-20
- Volume
- 31
- Issue
- 2
- Pages
- 200-212
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC5934994
- OpenAlex
- W2128926964
- Cited by
- 183
- References
- 53
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 13 · 2021: 14 · 2020: 20 · 2019: 27 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 13 · 2014: 16 · 2013: 4 · 2012: 12
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Institutes of Health (Z99 DE999999)
- National Institute of Dental and Craniofacial Research (Z01DE000438)
- Topics
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- TRPV4, arachidonic acid, endothelial cell migration, tumor angiogenesis, calcium influx, actin cytoskeleton remodeling, breast cancer, plasma membrane localization, intracellular calcium signaling, tumor-derived endothelial cells
- MeSH terms
- Actins, Cell Movement, Endothelium, Vascular, Humans, Neoplasms, Arachidonic Acid, TRPV Cation Channels
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