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Sci Signal. 2016 Oct 11;9(449):ra100. doi: 10.1126/scisignal.aaf6625.

Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels.

Author information

1
Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, M13 9NT, UK.
2
King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, Saint Thomas' Hospital, London, SE1 7EH, UK.
3
Department of Pharmacology, University of Vermont, Vermont, 05405-0068, USA.
4
Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen 4012, Hungary.
#
Contributed equally

Abstract

Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+ signals (Ca2+ sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries. We report that physiological intraluminal pressure within resistance arteries activated cGMP-dependent protein kinase (PKG) in VSMCs through oxidant-induced formation of an intermolecular disulfide bond between cysteine residues. Oxidant-activated PKG was required to trigger Ca2+ sparks, BK channel activity, and vasodilation in response to pressure. VSMCs from arteries from mice expressing a form of PKG that could not be activated by oxidants showed reduced Ca2+ spark frequency, and arterial preparations from these mice had decreased pressure-induced activation of BK channels. Thus, the absence of oxidative activation of PKG disabled the BK channel-mediated negative feedback regulation of vasoconstriction. Our results support the concept of a negative feedback control mechanism that regulates arterial diameter through mechanosensitive production of oxidants to activate PKG and enhance Ca2+ sparks.

PMID:
27729550
PMCID:
PMC5154376
DOI:
10.1126/scisignal.aaf6625
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no competing interests.

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