Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells.

HEBE A MENA; AGOSTINA CARESTIA; LEOPOLDINA SCOTTI; FERNANDA PARBORELL; MIRTA SCHATTNER; SOLEDAD NEGROTTO

JOURNAL OF THROMBOSIS AND HAEMOSTASIS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016

1538-7933

BACKGROUND:Extracellular histones are highly augmented in sites of neovessel formation, like regeneration tissues. Their cytotoxic effect has been studied in endothelial cells, although the mechanism involved and their action on late outgrowth endothelial progenitor cells (ECFC) remain unknown.OBJECTIVE:To study histone effect on ECFC survival and angiogenic functions and compare it with mature endothelial cells.METHODS AND RESULTS:Nuclear morphology analysis showed that each human recombinant histone triggered both apoptotic- and necrotic-like cell deaths in both mature and progenitor endothelial cells. While H1 and H2A exerted a weak toxicity, H2B, H3 and H4 were the most powerful. The percentage of apoptosis correlated with the percentage of ECFC exhibiting caspase-3 activation and was zeroed by the pan-caspase inhibitor Z-VAD-FMK. Necrotic-like cells death was also suppressed by this compound and the caspase-1 inhibitor Ac-YVAD-CMK, indicating that histones triggered ECFC pyroptosis. All histones, at non-cytotoxic concentrations, reduced migration and H2B, H3 and H4 induced cell cycle arrest and impaired tubulogenesis via p38 activation. Neutrophil-derived histones exerted similar effects. In vivo blood vessel formation in the quail chorioallantoic membrane was also reduced by H2B, H3 and H4. Their cytotoxic and antiangiogenic effects were suppressed by unfractioned and low molecular weight heparins and the combination of TLR2 and TLR4 blocking antibodies.CONCLUSIONS:Histones trigger both apoptosis and pyroptosis of ECFC and inhibit their angiogenic functions. Their cytotoxic and antiangiogenic effects are similar in mature endothelial cells and disappear after heparin addition or TLR2/TLR4 blockade, suggesting both as therapeutic strategies to improve tissue regeneration. This article is protected by copyright. All rights reserved.