Hydrogen sulphide and angiogenesis: mechanisms and applications

In vascular tissues, hydrogen sulphide (H(2)S) is mainly produced from L-cysteine by the cystathionine gamma-lyase (CSE) enzyme. Recent studies show that administration of H(2)S to endothelial cells in culture stimulates cell proliferation, migration and tube formation. In addition, administration of H(2)S to chicken chorioallantoic membranes stimulates blood vessel growth and branching. Furthermore, in vivo administration of H(2)S to mice stimulates angiogenesis, as demonstrated in the Matrigel plug assay. Pathways involved in the angiogenic response of H(2)S 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(2)S as an inhibitor of phosphodiesterases may play an additional role in its pro-angiogenic effect. The endogenous role of H(2)S 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(2)S. The pro-angiogenic effects of H(2)S are also apparent in vivo: in a model of hindlimb ischaemia-induced angiogenesis, H(2)S induces a marked pro-angiogenic response; similarly, in a model of coronary ischaemia, H(2)S exerts angiogenic effects. Angiogenesis is crucial in the early stage of wound healing. Accordingly, topical administration of H(2)S promotes wound healing, whereas genetic ablation of CSE attenuates it. Pharmacological modulation of H(2)S-mediated angiogenic pathways may open the door for novel therapeutic approaches.