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Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction.

ABSTRACT: Neuronal activity is thought to communicate to arterioles in the brain through astrocytic calcium (Ca(2+)) signaling to cause local vasodilation. Paradoxically, this communication may cause vasoconstriction in some cases. Here, we show that, regardless of the mechanism by which astrocytic endfoot Ca(2+) was elevated, modest increases in Ca(2+) induced dilation, whereas larger increases switched dilation to constriction. Large-conductance, Ca(2+)-sensitive potassium channels in astrocytic endfeet mediated a majority of the dilation and the entire vasoconstriction, implicating local extracellular K(+) as a vasoactive signal for both dilation and constriction. These results provide evidence for a unifying mechanism that explains the nature and apparent duality of the vascular response, showing that the degree and polarity of neurovascular coupling depends on astrocytic endfoot Ca(2+) and perivascular K(+).

SUBMITTER: Girouard H

PROVIDER: S-EPMC2840528 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction.

Girouard Hélène H Bonev Adrian D AD Hannah Rachael M RM Meredith Andrea A Aldrich Richard W RW Nelson Mark T MT

Proceedings of the National Academy of Sciences of the United States of America 20100202 8

Neuronal activity is thought to communicate to arterioles in the brain through astrocytic calcium (Ca(2+)) signaling to cause local vasodilation. Paradoxically, this communication may cause vasoconstriction in some cases. Here, we show that, regardless of the mechanism by which astrocytic endfoot Ca(2+) was elevated, modest increases in Ca(2+) induced dilation, whereas larger increases switched dilation to constriction. Large-conductance, Ca(2+)-sensitive potassium channels in astrocytic endfeet ...[more]

PMID: 20133576

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Project description:1. Little is known about serotonin (5-HT) receptors present on brain microvessels that are innervated by brainstem serotonergic neurons. Using 5-HT, sumatriptan and subtype selective 5-HT(1) receptor agonists and/or the 5-HT(1) receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (approximately 40--50 microm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N(omega)-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. 2. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD(2) values of 7.3+/-0.2 and 6.9+/-0.1); a response potently inhibited by GR127935 (pIC(50) value of 8.5+/-0.1) in bovine microvessels. 3. In both species, the 5-HT(1) receptor agonist sumatriptan induced a biphasic response consisting of a small but significant dilation at low concentrations (1 and/or 10 nM) followed by a constriction at higher doses (pD(2) for contraction of 6.9+/-0.1 and 6.6+/-0.2 in human and bovine vessels, respectively). Pre-incubation with L-NNA abolished the sumatriptan-induced dilation and significantly shifted the dose-response of the constriction curve to the left. In contrast, the selective 5-HT(1D) (PNU-109291) and 5-HT(1F) (LY344864) receptor agonists were devoid of any vasomotor effect. 4. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD(2) of 7.2+/-0.1 and 6.6+/-0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. 5. A significant negative correlation was observed between pial and intracortical vessels diameter and the extent of the dilatory response to 10(-9) M sumatriptan. Together, these results indicate that sumatriptan, most likely via activation of distinctly localized microvascular 5-HT(1B) receptors, can induce a constriction and/or a dilation which is sensitive to inhibition of NO synthesis and dependent on the size and, possibly, the existing tone of the vessels.

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Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction.

Publications

Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction.

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