LPS binding to HMGB1 promotes angiogenic behavior of endothelial cells through inhibition of p120 and CD31 via ERK/P38/Src signaling.

Lipopolysaccharide (LPS) is known to mediate angiogenic effects in endothelial cells. The underlying mechanisms, however, remain largely unknown. In this study, we showed that LPS induced high motility group box protein 1 (HMGB1) secretion in human pulmonary microvascular endothelial cells (HPMECs). Knockdown and overexpression of HMGB1 by adenoviral vectors effectively inhibited and promoted LPS-induced HPMEC migration and capillary-like tube formation, respectively. On the other hand, HMGB1 exerted an inhibitory effect on LPS-suppressed expression of platelet-endothelial cell adhesion molecule (CD31) and p120 catenin (p120); HMGB1 knockdown reversed this effect. These results suggest a functional synergy between LPS and HMGB1 in angiogenesis. Mechanistically, physical interaction of LPS with HMGB1 mediated dissociation of p120, β-catenin, and γ-catenin from vascular endothelial cadherin (VE-cadherin), but without affecting VE-cadherin expression. The synergistic effect of LPS and HMGB1 was closely associated with ERK/P38/Src signaling pathway, as evidenced by the reduced degree of migration and capillary-like tube formation in HPMECs treated with signaling pathway inhibitor. Collectively, our study shows a novel mechanism whereby LPS and HMGB1 synergistically regulate the angiogenic behavior of endothelial cells.