Fig. 13.

Various roles of H₂S in the stimulation of angiogenesis. H₂S can stimulate intracellular Ca²⁺ mobilization in endothelial cells, which stimulates eNOS via the calcium-calmodulin system. H₂S can activate PI3K/Akt pathway resulting in eNOS activation through phosphorylation at Ser1177. H₂S can also induce a direct posttranslational modification of eNOS via sulfhydration on Cys443. This action, in turn, can further activate and stabilizes eNOS by promoting its dimerization. H₂S can also stimulate the expression of eNOS mRNA, increasing eNOS protein levels. Further downstream, NO produced by eNOS binds to soluble guanylate cyclase (sGC) and induces the formation of cGMP. H₂S can inhibit PDE, suppressing the degradation of cGMP and increasing cGMP levels enhancing the activation of its downstream protein kinase, PKG. H₂S can open K_ATP channels on the endothelial cell membrane. H₂S can upregulate VEGF and its receptor through HI–F1α upregulation but also through Flt induction. H₂S can stimulate angiopoietin/tie system, possibly via the upregulation of Ang1, Ang2 and Tie. H₂S can also stimulate various endothelial cell receptors with pro-angiogenic roles, including VEGFR, CXCR1 and VCAM.