Hydrogen sulfide (H2S) is now considered as the third gaseotransmitter, however, the signaling pathways that modulate the biomedical effect of H2S on endothelial cells are poorly defined. In the present study, we found in human endothelial cells that H2S increased cell migration rates and induced a marked reorganization of the actin cytoskeleton, which was prevented by depletion of Rac1. Pharmacologic inhibiting vascular endothelial growth factor receptor (VEGFR) and phosphoinositide 3-kinase (PI3K) both blunted the activation of Rac1 and the promotion of cell migration induced by H2S. Moreover, H2S-induced Rac1 activation was selectively dependent on the presence of the PI3K p110α isoform. Activated Rac1 by H2S thus in turn resulted in the phosphorylation of the F-actin polymerization modulator, cofilin. Additionally, inhibiting of extracellular signal-regulated kinase (ERK) decreased the augmented cell migration rate by H2S, but had no effect on Rac1 activation. These results indicate that Rac1 conveys the H2S signal to microfilaments inducing rearrangements of actin cytoskeleton that regulates cell migration. VEGFR-PI3K was found to be upstream pathway of Rac1, while cofilin acted as a downstream effector of Rac1. ERK was also shown to be involved in the action of H2S on endothelial cell migration, but independently of Rac1.
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