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

Scott D. Zawieja, Jorge A. Castorena, Peichun Gui, Min Li, Simon A. Bulley, Jonathan Jaggar, Jason R. Rock, Michael J. Davis

Research output: Contribution to journalArticle

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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 isolatedmurine 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 inguinalaxillary 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.

Original languageEnglish (US)
Pages (from-to)532-554
Number of pages23
JournalJournal of General Physiology
Volume151
Issue number4
DOIs
StatePublished - Apr 1 2019

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Lymphatic Vessels
Action Potentials
Pressure
Muscle Cells
Smooth Muscle
Benzbromarone
Membrane Potentials
Transgenic Mice
Pharmacology

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Ano1 mediates pressure-sensitive contraction frequency changes in mouse lymphatic collecting vessels. / Zawieja, Scott D.; Castorena, Jorge A.; Gui, Peichun; Li, Min; Bulley, Simon A.; Jaggar, Jonathan; Rock, Jason R.; Davis, Michael J.

In: Journal of General Physiology, Vol. 151, No. 4, 01.04.2019, p. 532-554.

Research output: Contribution to journalArticle

Zawieja, SD, Castorena, JA, Gui, P, Li, M, Bulley, SA, Jaggar, J, Rock, JR & Davis, MJ 2019, 'Ano1 mediates pressure-sensitive contraction frequency changes in mouse lymphatic collecting vessels', Journal of General Physiology, vol. 151, no. 4, pp. 532-554. https://doi.org/10.1085/jgp.201812294
Zawieja, Scott D. ; Castorena, Jorge A. ; Gui, Peichun ; Li, Min ; Bulley, Simon A. ; Jaggar, Jonathan ; Rock, Jason R. ; Davis, Michael J. / Ano1 mediates pressure-sensitive contraction frequency changes in mouse lymphatic collecting vessels. In: Journal of General Physiology. 2019 ; Vol. 151, No. 4. pp. 532-554.
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