Hydrogen sulfide is an endogenous stimulator of angiogenesis
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abstract
The goal of the current study was to investigate the role of exogenous and endogenous hydrogen sulfide (H
2
S) on neovascularization and wound healing in vitro and in vivo. Incubation of endothelial cells (ECs) with H
2
S enhanced their angiogenic potential, evidenced by accelerated cell growth, migration, and capillary morphogenesis on Matrigel. Treatment of chicken chorioallantoic membranes (CAMS) with H
2
S increased vascular length. Exposure of ECs to H
2
S resulted in increased phosphorylation of Akt, ERK, and p38. The K
ATP
channel blocker glibenclamide or the p38 inhibitor SB203580 abolished H
2
S-induced EC motility. Since glibenclamide inhibited H
2
S-triggered p38 phosphorylation, we propose that K
ATP
channels lay upstream of p38 in this process. When CAMs were treated with H
2
S biosynthesis inhibitors dl-propylargylglycine or beta-cyano-L-alanine, a reduction in vessel length and branching was observed, indicating that H
2
S serves as an endogenous stimulator of the angiogenic response. Stimulation of ECs with vascular endothelial growth factor (VEGF) increased H
2
S release, while pharmacological inhibition of H
2
S production or K
ATP
channels or silencing of cystathionine gamma-lyase (CSE) attenuated VEGF signaling and migration of ECs. These results implicate endothelial H
2
S 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 H
2
S enhanced wound healing in a rat model, while wound healing was delayed in CSE
−/−
mice. We conclude that endogenous and exogenous H
2
S stimulates EC-related angiogenic properties through a K
ATP
channel/MAPK pathway.
