Mechanisms of angiogenesis: role of hydrogen sulphide.

1. Hydrogen sulphide (H(2)S) has recently been recognized as a gasotransmitter that regulates angiogenesis in vitro and in vivo under physiological and ischaemic conditions. 2. In the present review, the mechanisms underlying angiogenesis are summarized briefly and the most recent progress in H(2)S-induced angiogenesis in vivo and in vitro is described. The anti-angiogenic effects of garlic extracts, which may serve as substrates for H(2)S-generating enzymes in vivo, are also discussed. 3. Hydrogen sulphide increases cell growth, migration and the formation of tube-like structures in cultured endothelial cells. These effects are dependent on activation of the phosphatidylinositol 3-kinase-Akt-survivin signalling pathway. Neovascularization in vivo has also been demonstrated to be promoted in the mouse Matrigel plug assay, as well as in chicken chorioallantoic membranes. In a rat unilateral hindlimb ischaemic model, treatment with sodium hydrosulphide (NaHS), an H(2)S donor, promotes significant angiogenesis and improves regional blood flow. These effects may be mediated by interactions between upregulated vascular endothelial growth factor (VEGF) in skeletal muscle cells and VEGF receptor 2 and the downstream signalling element Akt in vascular endothelial cells. However, H(2)S does not exhibit a pro-angiogenic effect at a high concentrations/doses. 4. Based on the studies reviewed in the present article, we assume that, at physiologically relevant doses/concentrations, H(2)S/HS(-) promote angiogenesis at least partly via the VEGF signalling pathway. At high doses, H(2)S/HS(-) may act on additional cellular targets to evoke mechanisms that counteract the pro-angiogenic pathways. More studies need to be performed analysing the general interactions between H(2)S/HS(-) and other molecules, including other gasotransmitters, such as nitric oxide and carbon monoxide (CO).