Signaling Paradigms of H2S-Induced Vasodilation: A Comprehensive Review

Abstract

Hydrogen sulfide (H₂S), a gas traditionally considered toxic, is now recognized as a vital endogenous signaling molecule with a complex physiology. This comprehensive study encompasses a systematic literature review that explores the intricate mechanisms underlying H₂S-induced vasodilation. The vasodilatory effects of H₂S are primarily mediated by activating ATP-sensitive potassium (K_ATP) channels, leading to membrane hyperpolarization and subsequent relaxation of vascular smooth muscle cells (VSMCs). Additionally, H₂S inhibits L-type calcium channels, reducing calcium influx and diminishing VSMC contraction. Beyond ion channel modulation, H₂S profoundly impacts cyclic nucleotide signaling pathways. It stimulates soluble guanylyl cyclase (sGC), increasing the production of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels activate protein kinase G (PKG), which phosphorylates downstream targets like vasodilator-stimulated phosphoprotein (VASP) and promotes smooth muscle relaxation. The synergy between H₂S and nitric oxide (NO) signaling further amplifies vasodilation. H₂S enhances NO bioavailability by inhibiting its degradation and stimulating endothelial nitric oxide synthase (eNOS) activity, increasing cGMP levels and potent vasodilatory responses. Protein sulfhydration, a post-translational modification, plays a crucial role in cell signaling. H₂S S-sulfurates oxidized cysteine residues, while polysulfides (H₂Sn) are responsible for S-sulfurating reduced cysteine residues. Sulfhydration of key proteins like K_ATP channels and sGC enhances their activity, contributing to the overall vasodilatory effect. Furthermore, H₂S interaction with endothelium-derived hyperpolarizing factor (EDHF) pathways adds another layer to its vasodilatory mechanism. By enhancing EDHF activity, H₂S facilitates the hyperpolarization and relaxation of VSMCs through gap junctions between endothelial cells and VSMCs. Recent findings suggest that H₂S can also modulate transient receptor potential (TRP) channels, particularly TRPV4 channels, in endothelial cells. Activating these channels by H₂S promotes calcium entry, stimulating the production of vasodilatory agents like NO and prostacyclin, thereby regulating vascular tone. The comprehensive understanding of H₂S-induced vasodilation mechanisms highlights its therapeutic potential. The multifaceted approach of H₂S in modulating vascular tone presents a promising strategy for developing novel treatments for hypertension, ischemic conditions, and other vascular disorders. The interaction of H₂S with ion channels, cyclic nucleotide signaling, NO pathways, ROS (Reactive Oxygen Species) scavenging, protein sulfhydration, and EDHF underscores its complexity and therapeutic relevance. In conclusion, the intricate signaling paradigms of H₂S-induced vasodilation offer valuable insights into its physiological role and therapeutic potential, promising innovative approaches for managing various vascular diseases through the modulation of vascular tone.

Keywords: ROS scavenging; endothelial function; hydrogen sulfide (H2S); protein sulfhydration; vasodilation.

Figure 1

This figure illustrates the various molecular and signaling paradigms through which H₂S contributes to vasodilation: 1. Persulfidation Signaling—a post-translational modification where a sulfur atom is added to the thiol (-SH) group of cysteine residues, forming persulfide (-SSH) groups; 2. K_ATP Channel Activation Paradigm—reduces calcium influx, resulting in smooth muscle relaxation and vasodilation; 3. cGMP Pathway Activation Paradigm—elevated cGMP activates protein kinase G (PKG), which decreases intracellular calcium levels, causing smooth muscle relaxation and vasodilation; 4. Endothelial Nitric Oxide Synthase (eNOS) activation Paradigm; 5. Calcium Signaling Modulation Paradigm; 6. Redox Signaling and Antioxidant Effects Paradigm; 7. Interaction with Other Gasotransmitters Paradigm; 8. Endothelial-Dependent Hyperpolarization (EDH) Paradigm; 9. Interaction with Prostacyclin Signaling Paradigm; 10. Hypoxia Response Paradigm; 11. H₂S interaction with various transcription factors.