Hydrogen sulfide is an endogenous stimulator of angiogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (51), p.21972-21977
• Main Authors: Papapetropoulos, Andreas, Pyriochou, Anastasia, Altaany, Zaid, Yang, Guangdong, Marazioti, Antonia, Zhou, Zongmin, Jeschke, Mark G, Branski, Ludwik K, Herndon, David N, Wang, Rui, Szabó, Csaba
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal migration behavior; Apoptosis - drug effects; Biological Sciences; Cells; Cells, Cultured; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Humans; Hydrogen; Hydrogen sulfide; Hydrogen Sulfide - pharmacology; Membranes; Mice; Neovascularization, Physiologic - drug effects; Phosphorylation; Rodents; Signal Transduction - drug effects; Small interfering RNA; Sulfides; Vehicles; Wound healing; Wound Healing - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0908047106

The goal of the current study was to investigate the role of exogenous and endogenous hydrogen sulfide (H₂S) on neovascularization and wound healing in vitro and in vivo. Incubation of endothelial cells (ECs) with H₂S enhanced their angiogenic potential, evidenced by accelerated cell growth, migration, and capillary morphogenesis on Matrigel. Treatment of chicken chorioallantoic membranes (CAMS) with H₂S increased vascular length. Exposure of ECs to H₂S resulted in increased phosphorylation of Akt, ERK, and p38. The KATP channel blocker glibenclamide or the p38 inhibitor SB203580 abolished H₂S-induced EC motility. Since glibenclamide inhibited H₂S-triggered p38 phosphorylation, we propose that KATP channels lay upstream of p38 in this process. When CAMs were treated with H₂S biosynthesis inhibitors dl-propylargylglycine or beta-cyano-L-alanine, a reduction in vessel length and branching was observed, indicating that H₂S serves as an endogenous stimulator of the angiogenic response. Stimulation of ECs with vascular endothelial growth factor (VEGF) increased H₂S release, while pharmacological inhibition of H₂S production or KATP channels or silencing of cystathionine gamma-lyase (CSE) attenuated VEGF signaling and migration of ECs. These results implicate endothelial H₂S synthesis in the pro-angiogenic action of VEGF. Aortic rings isolated from CSE knockout mice exhibited markedly reduced microvessel formation in response to VEGF when compared to wild-type littermates. Finally, in vivo, topical administration of H₂S enhanced wound healing in a rat model, while wound healing was delayed in CSE⁻/⁻ mice. We conclude that endogenous and exogenous H₂S stimulates EC-related angiogenic properties through a KATP channel/MAPK pathway.