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


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.

SUBMITTER: Khavandi K 

PROVIDER: S-EPMC5154376 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Khavandi Kaivan K   Baylie Rachael A RA   Sugden Sarah A SA   Ahmed Majid M   Csato Viktoria V   Eaton Philip P   Hill-Eubanks David C DC   Bonev Adrian D AD   Nelson Mark T MT   Greenstein Adam S AS  

Science signaling 20161011 449


Activation of Ca<sup>2+</sup>-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca<sup>2+</sup> signals (Ca<sup>2+</sup> 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 oxida  ...[more]

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