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

See allHide authors and affiliations

Science Signaling  11 Oct 2016:
Vol. 9, Issue 449, pp. ra100
DOI: 10.1126/scisignal.aaf6625

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Dilating constricted resistance arteries

Small-diameter arteries called resistance arteries link the main arteries to capillary beds that feed tissues and organs. Resistance arteries may generate high blood pressure (hypertension) if they become persistently constricted. Khavandi et al. (see also Hill and Braun) found that constriction of resistance arteries triggered a signaling pathway that induced their dilation. Constriction stimulated the production of reactive oxygen species, which then oxidized and stimulated the kinase PKG. PKG triggered the generation of calcium sparks, which are short-lived, local increases in calcium. Calcium sparks activated a potassium channel that induces vasodilation. Thus, constriction of resistance arteries initiates a signal to ensure that these blood vessels return to a more dilated state.


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.

View Full Text

Stay Connected to Science Signaling