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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Kaivan Khavandi
  • Rachael L Baylie
  • Majid Ahmed
  • Viktoria Csato
  • Philip Eaton
  • David C Hill-Eubanks
  • Adrian D Bonev

Abstract

Activation of Ca(2+)-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca(2+) signals (Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) sparks.

Bibliographical metadata

Original languageEnglish
Pages (from-to)ra100
JournalScience Signaling
Volume9
Issue number449
Early online date11 Oct 2016
DOIs
Publication statusPublished - 2016

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