Cited by 70Lymphatic System and DiseasesIon Transport and Channel RegulationIon channel regulation and function

Ano1 mediates pressure-sensitive contraction frequency changes in mouse lymphatic collecting vessels

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Zawieja, Scott D., Castorena, Jorge A., Gui, Peichun, Li, Min, Bulley, Simon A., Jaggar, Jonathan H., Rock, Jason R., Davis, Michael J.·2019·Journal of General Physiology

Abstract

Lymphatic collecting vessels exhibit spontaneous contractions with a pressure-dependent contraction frequency. The initiation of contraction has been proposed to be mediated by the activity of a Ca2+-activated Cl− channel (CaCC). Here, we show that the canonical CaCC Anoctamin 1 (Ano1, TMEM16a) plays an important role in lymphatic smooth muscle pacemaking. We find that isolated murine lymphatic muscle cells express Ano1, and demonstrate functional CaCC currents that can be inhibited by the Ano1 inhibitor benzbromarone. These currents are absent in lymphatic muscle cells from Cre transgenic mouse lines targeted for Ano1 genetic deletion in smooth muscle. We additionally show that loss of functional Ano1 in murine inguinal-axillary lymphatic vessels, whether through genetic manipulation or pharmacological inhibition, results in an impairment of the pressure–frequency relationship that is attributable to a hyperpolarized resting membrane potential and a significantly depressed diastolic depolarization rate preceding each action potential. These changes are accompanied by alterations in action potential shape and duration, and a reduced duration but increased amplitude of the action potential–induced global “Ca2+ flashes” that precede lymphatic contractions. These findings suggest that an excitatory Cl− current provided by Ano1 is critical for mediating the pressure-sensitive contractile response and is a major component of the murine lymphatic action potential.

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  • In the mouse, genetic deletion of Ano1 from LMCs reduces basal contraction frequency to one-fourth of normal and blunts or abolishes pressure-induced chronotropy, but does not completely eliminate spontaneous contractions, suggesting at least one other ionic mechanism is involved.

    “In the mouse, genetic deletion of Ano1 from LMCs reduces basal contraction frequency to one-fourth of normal and blunts or abolishes pressure-induced chronotropy (55), but it does not completely eliminate spontaneous contractions, suggesting that at least one other ionic mechanism is involved (for a review, see 56).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [55]

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  • The slope of diastolic depolarization is highly dependent on the activity of ANO1 channels that are regulated by Ca2+ release from IP3R1-dependent stores.

    “The slope of diastolic depolarization is highly dependent on the activity of ANO1 channels (55) that are regulated by Ca2+ release from inositol trisphosphate receptor 1 (IP3R1)-dependent stores (80).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [55]

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Cited by

Sorted by citations

Authors
Zawieja, S. D., Castorena, J. A., Gui, P., Li, M., Bulley, S. A., Jaggar, J. H., Rock, J. R., & Davis, M. J.
Affiliations
  • University of Missouri (US)
  • Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 1
  • University of Tennessee Health Science Center (US)
  • Boston University (US)
Corresponding author
Davis, Michael J.
Venue
Journal of General Physiology
Published
2019-03-12
Volume
151
Issue
4
Pages
532-554
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
OpenAlex
W2921585179
Cited by
70
References
0
Citations by year
2026: 6 · 2025: 13 · 2024: 14 · 2023: 14 · 2022: 9 · 2021: 5 · 2020: 6 · 2019: 3
FWCI
2.40
Type
journal article
Language
en
Open access
Locations
  • The Journal of General Physiology (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01 HL122578, R01 HL125608, R01 HL133256, HL137745)
  • American Heart Association (16SDG27460007)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
TMEM16A, collecting lymphatic vessels, lymphatic smooth muscle, spontaneous contractions, contraction frequency, calcium-activated chloride channels, benzbromarone, resting membrane potential, diastolic depolarization, action potential
MeSH terms
Anoctamin-1, Animals, Benzbromarone, Calcium, Gene Expression Regulation, Male, Membrane Potentials, Mice, Transgenic, Pressure, Protein Conformation, Uricosuric Agents, Lymphatic Vessels, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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