Hydrogen sulfide promotes calcium signals and migration in tumor-derived endothelial cells

Abstract Hydrogen sulfide (H 2 S) is a gasotransmitter that plays several roles in various tissues, including the cardiovascular system. Because it has been recently proposed to act as a mediator of angiogenesis progression, here we investigate the effects of H 2 S in a well-established model of tumor angiogenesis: endothelial cells obtained from human breast carcinoma (B-TECs). Ca 2+ imaging and patch-clamp experiments reveal that acute perfusion with NaHS, a widely employed H 2 S donor, activates cytosolic calcium (Ca c ) increase, as well as potassium and nonselective cationic currents, in B-TECs. Stimulation with NaHS in the same concentration range (1 nM–200 μM) evoked Ca c signals also in “normal” human microvascular endothelial cells (HMVECs), but the amplitude was significantly lower. Moreover, although NaHS failed to promote either migration or proliferation on HMVECs, B-TEC migration was enhanced at low-micromolar NaHS concentrations (1–10 μM). Remarkably H 2 S mediates tumor proangiogenic signaling triggered by vascular endothelial growth factor (VEGF). B-TECs pretreated with dl -propargylglycine (5 mM, 30 min), an inhibitor of the H 2 S-producing enzyme cystathionine γ-lyase, showed drastically reduced migration and Ca c signals induced by VEGF (20 ng/ml). We conclude that H 2 S plays a role in proangiogenic signaling of tumor-derived but not normal human ECs. Furthermore the ability of this gasotransmitter to interfere with B-TEC responsiveness to VEGF suggests that it could be an interesting target for antiangiogenic strategies in tumor treatment.