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Dilates Cerebral Arteries via NAD(P)H Oxidase-Dependent Ca2+Spark Activation
1 Physiology, University of Tennessee, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: jjaggar{at}physio1.utmem.edu.
Expression of Tumor Necrosis Factor alpha (TNF-
), a pleiotropic cytokine, is elevated during stroke and cerebral ischemia. TNF- regulates arterial diameter, although mechanisms mediating this effect are unclear. Here, we tested the hypothesis that TNF- regulates the diameter of resistance-size (~150 µm diameter) cerebral arteries by modulating local and global intracellular calcium (Ca2+) signals in smooth muscle cells. Laser-scanning confocal imaging revealed that TNF- increased Ca2+ spark and Ca2+ wave frequency, but reduced global Ca2+ concentration ([Ca2+]i) in smooth muscle cells of intact arteries. TNF- elevated reactive oxygen species (ROS) in smooth muscle cells of intact arteries and this was prevented by apocynin or diphenyleneiodonium (DPI), NAD(P)H oxidase blockers, but was unaffected by inhibitors of other ROS generating enzymes. In voltage-clamped (-40 mV) cells, TNF- increased the frequency and amplitude of Ca2+ spark-induced large-conductance Ca2+-activated potassium (KCa) channel transients ~1.7-fold and ~1.4-fold, respectively. TNF--induced transient KCa current activation was reversed by apocynin or MnTMPyP, a membrane-permeant antioxidant, and prevented by intracellular dialysis of catalase. TNF- induced reversible and similar amplitude dilations in either endothelium-intact or -denuded pressurized (60 mm Hg) cerebral arteries. MnTMPyP, thapsigargin, a sarcoplasmic reticulum Ca2+ ATP-ase blocker that inhibits Ca2+ sparks, and iberiotoxin, a KCa channel blocker, reduced TNF--induced vasodilations to between 15 and 33% of control. In summary, data indicate that TNF- activates NAD(P)H oxidase, resulting in an increase in intracellular H2O2 that stimulates Ca2+ sparks and transient KCa currents, leading to a reduction in global [Ca2+]i, and vasodilation.
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