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

Hydrogen sulfide (H2S) 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 H2S in a well-established model of tumor angiogenesis: endothelial cells obtained from human breast carcinoma (B-TECs). Ca2+ imaging and patch-clamp experiments reveal that acute perfusion with NaHS, a widely employed H2S 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 mu M) 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 mu M). Remarkably H2S 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 H2S-producing enzyme cystathionine gamma-lyase, showed drastically reduced migration and Ca-c signals induced by VEGF (20 ng/ml). We conclude that H2S 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. (C) 2011 Elsevier Inc. All rights reserved.