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Cited by 70Barrier Structure and Function StudiesIon Transport and Channel RegulationIon Channels and Receptors

TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress

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Hicks, Kali, O'Neil, Roger G., Dubinsky, William S., Brown, Rachel C.·2010·American Journal of Physiology-Cell Physiology
DOI 10.1152/ajpcell.00458.2009PMC PMC2889642
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Abstract

Hypoxia-induced disruption of the blood-brain barrier (BBB) is the result of many different mechanisms, including alterations to the cytoskeleton. In this study, we identified actin-binding proteins involved in cytoskeletal dynamics with quantitative proteomics and assessed changes in subcellular localization of two proteins involved in actin polymerization [vasodilator-stimulated phosphoprotein (VASP)] and cytoskeleton-plasma membrane cross-linking (moesin). We found significant redistribution of both VASP and moesin to the cytoskeletal and membrane fractions of BBB endothelial cells after 1-h hypoxic stress. We also investigated activation of actin-myosin contraction through assessment of phosphorylated myosin light chain (pMLC) with confocal microscopy. Hypoxia caused a rapid and transient increase in pMLC. Blocking MLC phosphorylation through inhibition of myosin light chain kinase (MLCK) with ML-7 prevented hypoxia-induced BBB disruption and relocalization of the tight junction protein ZO-1. Finally, we implicate the transient receptor potential (TRP)C family of channels in mediating these events since blockade of TRPC channels and the associated calcium influx with SKF-96365 prevents hypoxia-induced permeability changes and the phosphorylation of MLC needed for actin-myosin contraction. These data suggest that hypoxic stress triggers alterations to cytoskeletal structure that contribute to BBB disruption and that calcium influx through TRPC channels contributes to these events.

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  • Abluminal transient receptor potential (TRP) channels are expressed both in arterial endothelium and brain microvascular endothelial cell lines.

    “The abluminal transient receptor potential (TRP) channels, also known as nonselective Ca 2 + -conducting cation channels, are expressed both in arterial endothelium (553) and brain microvascular endothelial cell lines (38, 249).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [249]

    The Results report functional TRPC and TRPV channels in brain endothelial cells, and Materials and Methods identifies the cells used as an immortalized mouse brain endothelial cell line. The paper does not establish that these channels are abluminal. The arterial-endothelium portion is attached to a different citation (553), not this source. (LLM, conf=0.83)

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Authors
Hicks, K., O'Neil, R. G., Dubinsky, W. S., & Brown, R. C.
Affiliations
  • The University of Texas Health Science Center at Houston (US)
  • Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas
Corresponding author
Brown, Rachel C.
ORCID
Brown, Rachel C.
Venue
American Journal of Physiology-Cell Physiology
Publisher
American Physiological Society
Published
2010-06
Volume
298
Issue
6
Pages
C1583-C1593
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
DOI
10.1152/ajpcell.00458.2009
PMC
PMC2889642
OpenAlex
W2125958944
Cited by
70
References
2
Citations by year
2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 8
FWCI
4.46
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-70950, R01DK070950)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
blood-brain barrier disruption, hypoxia, TRPC channels, endothelial cells, VASP, moesin, myosin light chain phosphorylation, myosin light chain kinase, ZO-1, tight junctions, calcium influx, cytoskeletal dynamics, blood-brain barrier permeability
MeSH terms
Vasodilator-Stimulated Phosphoprotein, Actins, Animals, Azepines, Blood-Brain Barrier, Calcium, Calcium Channel Blockers, Cell Line, Enzyme Inhibitors, Imidazoles, Microfilament Proteins, Myosins, Myosin-Light-Chain Kinase, Naphthalenes, Permeability, Phosphoproteins, Phosphorylation, Stress, Physiological, Time Factors, Cell Hypoxia, Cell Adhesion Molecules, Myosin Light Chains, Tight Junctions, Protein Transport, Proteomics, Endothelial Cells, Cell Shape, TRPC Cation Channels, Mice

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