H₂S is an endothelium-derived hyperpolarizing factor

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Endocrinology

Background:

• Endothelium-dependent vasodilation involves endothelium-derived relaxing factor and endothelium-derived hyperpolarizing factor (EDHF).
• The precise molecular identity of EDHF has remained elusive.
• Understanding EDHF mechanisms is crucial for vascular health.

Purpose of the Study:

• To investigate if hydrogen sulfide (H₂S) functions as an EDHF.
• To elucidate the pathway through which H₂S mediates EDHF effects from endothelial cells to smooth muscle cells.

Main Methods:

• Utilized cystathionine γ-lyase (CSE)-knockout (KO) mice to assess H₂S's role.
• Measured smooth muscle cell (SMC) membrane potential and vasorelaxation responses.
• Employed pharmacological agents to block specific ion channels and signaling pathways.
• Administered exogenous H₂S to evaluate its direct effects.

Main Results:

• CSE-knockout mice exhibited elevated SMC resting membrane potential and abolished methacholine-induced vasodilation in mesenteric arteries.
• Methacholine induced SMC hyperpolarization in wild-type mesenteric arteries, an effect dependent on H₂S and small-conductance KCa (SKCa) channels.
• Exogenous H₂S replicated the hyperpolarizing effects of methacholine in both wild-type and CSE-KO tissues.
• H₂S upregulated SK2.3 channel expression, suggesting a mechanism for its EDHF activity.

Conclusions:

• Hydrogen sulfide (H₂S) is identified as an endothelium-derived hyperpolarizing factor (EDHF).
• This discovery resolves a significant question regarding the mechanisms of endothelium-dependent vasodilation.
• H₂S presents a potential therapeutic target for vascular diseases affecting peripheral resistance arteries.