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2000
Volume 23, Issue 9
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Introduction

The gasotransmitter hydrogen sulfide (HS) modulates various brain functions, including neuron excitability, synaptic plasticity, and Ca2+ dynamics. Furthermore, HS may stimulate nitric oxide (NO) release from cerebrovascular endothelial cells, thereby regulating NO-dependent endothelial functions, such as angiogenesis, vasorelaxation, and cerebral blood flow (CBF). However, the signaling pathway by which HS induces NO release from cerebrovascular endothelial cells is still unclear.

Methods

Herein, we exploited single-cell imaging of intracellular Ca2+, HS, and NO levels to assess how HS induces Ca2+-dependent NO release from the human cerebrovascular endothelial cell line, hCMEC/D3.

Results

Administration of the HS donor, sodium hydrosulfide (NaHS), induced a dose-dependent increase in (Ca2+) only in the presence of extracellular Ca2+. NaHS-induced extracellular Ca2+ entry was mediated by the Ca2+-permeable TRPA1 channel, as shown by pharmacological and genetic manipulation of the TRPA1 protein. Furthermore, NaHS-dependent TRPA1 activation led to NO release that was abolished by buffering the concomitant increase in (Ca2+) and inhibiting eNOS. Furthermore, the endothelial agonist, adenosine trisphosphate (ATP), caused a long-lasting elevation in (Ca2+) that was driven by cystathionine γ-lyase (CSE)-dependent HS production and by TRPA1 activation. Consistent with this, ATP-induced NO release was strongly reduced either by blocking CSE or by inhibiting TRPA1.

Conclusion

These findings demonstrate for the time that HS stimulates TRPA1 to induce NO production in human brain microvascular endothelial cells. Additionally, they show that this signaling pathway can be recruited by an endothelial agonist to modulate NO-dependent events at the human neurovascular unit.

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Transient Receptor Potential Ankyrin 1 (TRPA1) Mediates Hydrogen Sulfide-induced Ca2+ Entry and Nitric Oxide Production in Human Cerebrovascular Endothelium
Curr. Neuropharmacol. 23, 1119 (2025); https://doi.org/10.2174/011570159X349872250124124612
/content/journals/cn/10.2174/011570159X349872250124124612
/content/journals/cn/10.2174/011570159X349872250124124612
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  • Article Type:     Research Article
Keyword(s): ATP; Ca2+ signaling; cystathionine γ-lyase; hCMEC/D3 cells; Hydrogen sulfide; nitric oxide; TRPA1

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