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Hydrogen sulphide (H 2 S) is a newly discovered gasotransmitter that regulates multiple steps in VEGF-induced angiogenesis. An increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) is central to endothelial proliferation and may be triggered by both VEGF and H 2 S. Albeit VEGFR-2 might serve as H 2 S receptor, the mechanistic relationship between VEGF- and H 2 S-induced Ca 2+ signals in endothelial cells is unclear. The present study aimed at assessing whether and how NaHS, a widely employed H 2 S donor, stimulates pro-angiogenic Ca 2+ signals in Ea.hy926 cells, a suitable surrogate for mature endothelial cells, and human endothelial progenitor cells (EPCs). We found that NaHS induced a dose-dependent increase in [Ca 2+ ] i in Ea.hy926 cells. NaHS-induced Ca 2+ signals in Ea.hy926 cells did not require extracellular Ca 2+ entry, while they were inhibited upon pharmacological blockade of the phospholipase C/inositol-1,4,5-trisphosphate (InsP 3 ) signalling pathway. Moreover, the Ca 2+ response to NaHS was prevented by genistein, but not by SU5416, which selectively inhibits VEGFR-2. However, VEGF-induced Ca 2+ signals were suppressed by dl -propargylglycine (PAG), which blocks the H 2 S-producing enzyme, cystathionine γ-lyase. Consistent with these data, VEGF-induced proliferation and migration were inhibited by PAG in Ea.hy926 cells, albeit NaHS alone did not influence these processes. Conversely, NaHS elevated [Ca 2+ ] i only in a modest fraction of circulating EPCs, whereas neither VEGF-induced Ca 2+ oscillations nor VEGF-dependent proliferation were affected by PAG. Therefore, H 2 S-evoked elevation in [Ca 2+ ] i is essential to trigger the pro-angiogenic Ca 2+ response to VEGF in mature endothelial cells, but not in their immature progenitors.

Hydrogen sulphide (H2S) is a newly discovered gasotransmitter that regulates multiple steps in VEGF-induced angiogenesis. An increase in intracellular Ca(2+) concentration ([Ca(2+)]i) is central to endothelial proliferation and may be triggered by both VEGF and H2S. Albeit VEGFR-2 might serve as H2S receptor, the mechanistic relationship between VEGF- and H2S-induced Ca(2+) signals in endothelial cells is unclear. The present study aimed at assessing whether and how NaHS, a widely employed H2S donor, stimulates pro-angiogenic Ca(2+) signals in Ea.hy926 cells, a suitable surrogate for mature endothelial cells, and human endothelial progenitor cells (EPCs). We found that NaHS induced a dose-dependent increase in [Ca(2+)]i in Ea.hy926 cells. NaHS-induced Ca(2+) signals in Ea.hy926 cells did not require extracellular Ca(2+) entry, while they were inhibited upon pharmacological blockade of the phospholipase C/inositol-1,4,5-trisphosphate (InsP3) signalling pathway. Moreover, the Ca(2+) response to NaHS was prevented by genistein, but not by SU5416, which selectively inhibits VEGFR-2. However, VEGF-induced Ca(2+) signals were suppressed by dl-propargylglycine (PAG), which blocks the H2S-producing enzyme, cystathionine γ-lyase. Consistent with these data, VEGF-induced proliferation and migration were inhibited by PAG in Ea.hy926 cells, albeit NaHS alone did not influence these processes. Conversely, NaHS elevated [Ca(2+)]i only in a modest fraction of circulating EPCs, whereas neither VEGF-induced Ca(2+) oscillations nor VEGF-dependent proliferation were affected by PAG. Therefore, H2S-evoked elevation in [Ca(2+)]i is essential to trigger the pro-angiogenic Ca(2+) response to VEGF in mature endothelial cells, but not in their immature progenitors.