Hydrogen Sulfide Treatment Induces Angiogenesis After Cerebral Ischemia

Abstract

Hydrogen sulfide (H2S) is a potent vasodilator and regulates cardiovascular homeostasis. Furthermore, H2S has a crucial role in ischemiareperfusion injuries, especially of the heart, liver and kidneys. In this study, we suggest that post-treatment with hydrogen sulfide is able to recover neurological function after ischemic stroke by promoting angiogenesis. Posttreatment with H2S augments angiogenesis at the peri-infarct area, and it significantly improves functional outcomes after 2 weeks in a rat model of transient middle cerebral artery occlusion (MCAO). H2S promotes the phosphorylation of AKT and extracellular signal-regulated kinase (ERK) and increases the expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1). H2S-treated rats showed more newly synthesized endothelial cells in the ischemic lesion (2.31-fold, p<0.01). H2S-treated astrocytes increased VEGF and Ang-1 expression, and the inhibition of phosphatidylinositide 3-kinase (PI3K)/AKT signaling by LY294002 significantly reduced H2S-induced VEGF and Ang-1 expression in astrocytes. Finally, H2S stimulated endothelial cells migration (3.92-fold increase of wound healing assay) and tube formation (3.69-fold increase, p<0.001) through PI3K/AKT signaling. In conclusion, post-treatment with H2S promotes angiogenesis and thereby contributes to improvement of functional outcome after cerebral ischemia. Our findings strongly suggest that H2S may be of value in regenerative recovery after stroke.