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

MENA HA; CARESTIA A; SCOTTI L,; PARBORELL FERNANDA; SCHATTNER M; NEGROTTO S

JOURNAL OF THROMBOSIS AND HAEMOSTASIS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2016 p. 397 - 410

1538-7933

Essentials Extracellular histones are highly augmented in sites of neovesselformation, such as regeneration tissues. We studied histone effect on survivaland angiogenic activity of mature and progenitor endothelial cells. Extracellular histones trigger apoptosis and pyroptosis and reduce angiogenesis in vivo and in vitro. Histone blockade can be useful as a therapeutic strategy to improve angiogenesis and tissue regeneration.SUMMARY: 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 endothelial colony-forming cells (ECFCs) remain unknown. Objective To study the effect of histones 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-like 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 ECFCs exhibiting caspase-3 activation and was zeroed by the pan-caspase inhibitor Z-VAD-FMK. Necrotic-like cell death was also suppressed by this compound and the caspase-1 inhibitor Ac-YVAD-CMK, indicating that histonestriggered ECFC pyroptosis. All histones, at non-cytotoxic concentrations, reducedmigration and H2B, H3 and H4 induced cell cycle arrest and impaired tubulogenesisvia 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 byunfractioned and low-molecular-weight heparins and the combination of TLR2 andTLR4 blocking antibodies. Conclusions Histones trigger both apoptosis andpyroptosis of ECFCs and inhibit their angiogenic functions. Their cytotoxic andantiangiogenic effects are similar in mature endothelial cells and disappearafter heparin addition or TLR2/TLR4 blockade, suggesting both as therapeuticstrategies to improve tissue regeneration.