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Distinct EC coupling mechanism drives spatial control of vascular tone in cerebral arteries
Author(s) -
Zechariah Anil,
Hald Bjorn Olav,
Mazumdar Neil G.,
Welsh Donald 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.945.10
Subject(s) - cerebral blood flow , coupling (piping) , myosin light chain kinase , biophysics , myosin , blood flow , phosphorylation , stimulus (psychology) , chemistry , neuroscience , anatomy , biology , medicine , materials science , biochemistry , psychology , psychotherapist , metallurgy
Cerebral arterial networks consist of thousands of segments that work together and in isolation, tuning the magnitude and distribution of brain blood flow. The existence of spatially distinct responses suggests that distinct excitation‐contraction (EC) coupling mechanisms are encoded into each arterial segment. This study sought to define which EC coupling mechanisms enable cerebral arterial segments to work together and in isolation, from one another. Using both theoretical and experimental approaches, we show that multi‐segmental responses require the sharing of charge via gap junctions. This process of “electrical communication” enables arteries to equilibrate membrane potential, synchronize Ca 2+ concentration and coordinate myosin light chain phosphorylation among large populations of smooth muscle cells. In contrast, isolated vessel behavior was independent of charge sharing and electromechanical coupling. It depended upon: 1) the voltage‐independent generation of Ca 2+ waves; and 2) direct catalytic subunit inhibition of myosin light chain phosphatase. The latter was found to be driven by protein kinase C and the phosphorylation of CPI‐17. Subsequent work revealed that the presence of distinct EC coupling mechanisms enabled multi‐segmental and isolated responses to simultaneously but independently co‐exist in a single artery. As such, the magnitude and distribution of brain blood flow can be concurrently tuned depending on the nature of the originating stimulus. Translationally, these findings indicate that the ‘one‐size‐fits‐all” strategy to treating blood flow abnormalities should be reconsidered and tailored to the underlying dysfunction in EC coupling. Support or Funding Information This work is supported by an operating grant to Dr Welsh from the Natural Science and Engineering Council of Canada (NSERC). Dr Welsh is the Roraback Chair in Neuroscience and Vascular Biology at the University of Western Ontario. A. Zechariah is supported by Canadian Institutes of Health Research (CIHR) Postdoctoral scholarship, Alberta Innovates Postdoctoral scholarship and Eyes High Postdoctoral fellowship.