Regulation and role of endogenously produced hydrogen sulfide in angiogenesis

Recent studies have implicated endogenously produced H₂S in the angiogenic process. On one hand, pharmacological inhibition and silencing of the enzymes involved in H₂S synthesis attenuate the angiogenic properties of endothelial cells, including proliferation, migration and tube-like structure network formation. On the other hand, enhanced production of H₂S by substrate supplementation or over-expression of H₂S-producing enzymes leads to enhanced angiogenic responses in cultured endothelial cells. Importantly, H₂S up-regulates expression of the key angiogenic factor vascular endothelial growth factor (VEGF) and contributes to the angiogenic signaling in response to VEGF. The signaling pathways mediating H₂S-induced angiogenesis include mitogen-activated protein kinases, phosphoinositide-3 kinase, nitric oxide/cGMP-regulated cascades and ATP-sensitive potassium channels. Endogenously produced H₂S has also been shown to facilitate neovascularization in prototypical model systems in vivo, and to contribute to wound healing, post-ischemic angiogenesis in the heart and other tissues, as well as in tumor angiogenesis. Targeting of H₂S synthesizing enzymes might offer novel therapeutic opportunities for angiogenesis-related diseases.