Introduction Angiogenesis is a key process in a variety of biological processes ranging from wound healing to tumor biology. Hydrogen sulfide (H 2 S) and nitric oxide (NO) are recognized as essential, interacting, endogenous gaseous signaling molecules. Here we review the existing data demonstrating the effect of exogenous and endogenous H 2 S on angiogenesis and overview the molecular pathways involved. We are also presenting a range of therapeutic context where these mechanisms can be exploited in the future. Methods Murine bEnd.3 endothelial cells were used for in vitro studies; burn-induced wound healing in rats and mice was used for in vivo studies. Results Exposure of endothelial cells to a H 2 S donor increased intracellular cGMP in a NO-dependent manner, activated protein kinase G (PKG) and induced the phosphorylation of its downstream substrate, VASP. Inhibition of eNOS or PKG abolished the H 2 S-stimulated angiogenic response. Thus, there is a convergence of the vascular actions of H 2 S and NO to the cGMP/PKG pathway. Silencing of the H 2 S-producing enzyme cystathionine-gamma-lyase (CSE) abolished NO-stimulated cGMP accumulation and angiogenesis, indicating the requirement of H 2 S in the vascular actions of NO. VEGF, a pro-angiogenic and vasorelaxant hormone stimulated the production of both NO and H 2 S: VEGF-induced angiogenic and vasorelaxant responses were attenuated either by the inhibition of NO or by the silencing of CSE. A key site of the cooperative interaction between NO and H 2 S involves the cGMP/PKG pathway: H 2 S exerted a potent inhibitory effect on phosphodiesterase 5 activity in vitro leading to cGMP elevation and PKG activation. Another site of the interaction between H 2 S and NO is Akt: H 2 S increased the phosphorylation (activation) of Akt, as well as the phosphorylation of eNOS at Ser1177. In vivo H 2 S administration promoted post-burn wound healing, while reduced H 2 S production (mice deficient in CSE) delayed it. H 2 S -mediated and angiogenesis in vivo was suppressed by pharmacological inhibition (L-NAME) or genetic ablation of eNOS (eNOS −/− mice). Conclusions H 2 S is a pro-angiogenic endogenous hormone. Administration of H 2 S promotes wound healing. NO and H 2 S are mutually required for the control of angiogenesis and wound healing. H 2 S supplementation may be beneficial to facilitate post-burn wound healing. Potential modes of delivery may include topical or systemic administration. However, the angiogenic effect of H 2 S is not expected to be optimal in conditions where endogenous NO production is impaired (i.e. conditions associated with endothelial dysfunction syndrome). In such conditions, simultaneous supplementation of both gasotransmitters may be possible. In addition to wound healing, the pro-angiogenic effects of H 2 S may be utilized to improve revascularization following ischemic conditions, whereas inhibition of H 2 S production (and associated angiogenic responses) may be of therapeutic interest in conditions associated with pathological increases in angiogenesis (e.g. in the context of tumor angiogenesis or in diabetic retinopathy).
Read full abstract