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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.

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


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.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no competing interests.

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