Role of Hydrogen Sulfide and Hypoxia in Hepatic Angiogenesis of Portal Hypertension

Abstract

The pathogenesis of portal hypertension remains unclear, and is believed to involve dysfunction of liver sinusoidal endothelial cells (LSEC), activation of hepatic stellate cells (HSC), dysregulation of endogenous hydrogen sulfide (H₂S) synthesis, and hypoxia-induced angiogenic responses. H₂S, a novel gas transmitter, plays an important role in various pathophysiological processes, especially in hepatic angiogenesis. Inhibition of endogenous H₂S synthase by pharmaceutical agents or gene silencing may enhance the angiogenic response of endothelial cells. Hypoxia-inducible factor-1 (HIF-1) is the main transcription factor of hypoxia, which induces hepatic angiogenesis through up-regulation of vascular endothelial growth factor (VEGF) in HSC and LSEC. H₂S has also been shown to be involved in the regulation of VEGF-mediated angiogenesis. Therefore, H₂S and HIF-1 may be potential therapeutic targets for portal hypertension. The effects of H₂S donors or prodrugs on the hemodynamics of portal hypertension and the mechanism of H₂S-induced angiogenesis are promising areas for future research.

Keywords: Angiogenesis; Hydrogen sulfide; Hypoxia; Hypoxia-inducible factor; Portal hypertension.

Fig. 1. Pathways of HIF-1α synthesis/degradation under normoxic and hypoxic conditions.

Translation of HIF-1α protein under normoxic conditions is mainly dependent on the activation of PI3K/Akt/mTOR signaling pathway. HIF-1α is hydroxylated by PHD under normoxic conditions and subsequently binds to VHL protein to form a complex. The complex in turn recruits ubiquitin ligases to target HIF-1α for proteasomal degradation. Under hypoxic conditions, H₂S induces phosphorylation of eIF2α, thereby inhibiting HIF-1α translation. In addition, H₂S reverses hypoxia-induced inhibition of PHD activity and thus promotes the degradation of HIF-1α. HIF-1α, hypoxia-inducible factor 1α; PHD, prolyl hydroxylase; VHL, von Hippel-Lindau; H₂S, hydrogen sulfide; eIF2α, eukaryotic translation initiation factor 2α.

Fig. 2. Proposed interactions among H₂S, VEGF, and HIF-1.

The binding of VEGF to VEGFR2 may activate CSE through a calcium-dependent pathway, which in turn promotes endogenous H₂S production. Nucleophilic attack by H₂S on the disulfide bond between Cys 1045-1024 leads to reduction of the disulfide bond and enhances VEGFR2 tyrosine kinase activity. CBS-derived and CSE-derived H₂S enhances the stability and transcriptional activity of Sp1, which further promotes the transcription of VEGFR2. H₂S results in increased HIF-1α levels, DNA binding, and transcriptional activity. VEGFR2, vascular endothelial growth factor receptor 2; VEGF, vascular endothelial growth factor; CSE, cystathionine-γ lyase; CBS, cystathionine-β synthase; HIF, hypoxia-inducible factor; HRE, hypoxia response element; Sp1, specificity protein 1; H₂S, hydrogen sulfide.