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Acetylcholine Released by the Endothelium Mediates Flow‐induced Endothelial Ca 2+ Signalling and Vascular Relaxation
Author(s) -
Wilson Calum,
SanchezSantos Manuel,
McCarron John G
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1204.1
Subject(s) - vasodilation , chemistry , endothelium , acetylcholine , nitric oxide , extracellular , biophysics , microbiology and biotechnology , endocrinology , biochemistry , biology , organic chemistry
The flow of blood generates mechanical forces (e.g. shear‐stress) that are important physiological regulators of vascular tone. The vascular endothelium senses these forces and, in response, releases various vasodilators (e.g. nitric oxide) that relax smooth muscle cells in a process termed flow‐mediated vasodilation. Whilst some elements of the signalling mechanisms have been identified, precisely how flow is sensed and then transduced to cause the release of relaxing factors is poorly understood. In intact, pressurized arteries we show that flow induces relaxation of phenylephrine‐induced contractions. In large areas of the endothelium of surgically opened arteries, encompassing ~150 cells, flow (shear‐stress: 3 dyne cm −2 ) induced endothelial Ca 2+ signalling and the release of nitric oxide. The Ca 2+ signals were complex and transmitted between cells as intercellular “waves”, resulting in spatiotemporally heterogeneous activity across the endothelium. The Ca 2+ signals were evoked both by IP 3 ‐mediated Ca 2+ release and Ca 2+ influx from the extracellular space. Both components of the Ca 2+ signals (release and influx) arose from the activation of the endothelium by acetylcholine (ACh) released in response to shear‐stress. In support, flow‐induced Ca 2+ signals were abolished by atropine and by acetylcholinesterase. The flow‐induced Ca 2+ signals were also attenuated by the choline acetyltransferase inhibitor, bromoacetylcholine, and potentiated by the acetylcholinesterase inhibitor, neostigmine. Flow‐induced responses were also blocked by depolarization and by inhibitors of chloride channels, but were unaffected by inhibitors of ATP‐mediated signalling pathways, organic cation transporters, or Panx hemichannels. Together, these results suggest that physiological shear‐stress induced activation of endothelial chloride channels mediates the release of ACh and hence flow‐mediated vasodilation. Significantly, these results also suggest that ACh is an autocrine signalling molecule released from endothelial cells. Support or Funding Information Supported by the Wellcome Trust and the British Heart Foundation