Hydrogen sulphide and angiogenesis: Mechanisms and applications

In vascular tissues, hydrogen sulphide (H ₂S) is mainly produced from L-cysteine by the cystathionine gamma-lyase (CSE) enzyme. Recent studies show that administration of H ₂S to endothelial cells in culture stimulates cell proliferation, migration and tube formation. In addition, administration of H ₂S to chicken chorioallantoic membranes stimulates blood vessel growth and branching. Furthermore, in vivo administration of H ₂S to mice stimulates angiogenesis, as demonstrated in the Matrigel plug assay. Pathways involved in the angiogenic response of H ₂S include the PI-3K/Akt pathway, the mitogen activated protein kinase pathway, as well as ATP-sensitive potassium channels. Indirect evidence also suggests that the recently demonstrated role of H ₂S as an inhibitor of phosphodiesterases may play an additional role in its pro-angiogenic effect. The endogenous role of H ₂S in the angiogenic response has been demonstrated in the chicken chorioallantoic membranes, in endothelial cells in vitro and ex vivo. Importantly, the pro-angiogenic effect of vascular endothelial growth factor (but not of fibroblast growth factor) involves the endogenous production of H ₂S. The pro-angiogenic effects of H ₂S are also apparent in vivo: in a model of hindlimb ischaemia-induced angiogenesis, H ₂S induces a marked pro-angiogenic response; similarly, in a model of coronary ischaemia, H ₂S exerts angiogenic effects. Angiogenesis is crucial in the early stage of wound healing. Accordingly, topical administration of H ₂S promotes wound healing, whereas genetic ablation of CSE attenuates it. Pharmacological modulation of H ₂S-mediated angiogenic pathways may open the door for novel therapeutic approaches.