title: Histamine synergistically promotes bFGF-induced angiogenesis by enhancing VEGF production via H1 receptor.
abstract: Histamine, a major mediator present in mast cells that is released into the extracellular milieu upon degranulation, is well known to possess a wide range of biological activities in several classic physiological and pathological processes. However, whether and how it participates in angiogenesis remains obscure. In the present study, we observed its direct and synergistic action with basic fibroblast growth factor (bFGF), an important inducer of angiogenesis, on in vitro angiogenesis models of endothelial cells. Data showed that histamine (0.1, 1, 10 µM) itself was absent of direct effects on the processes of angiogenesis, including the proliferation, migration, and tube formation of endothelial cells. Nevertheless, it could concentration-dependently enhance bFGF-induced angiogenesis as well as production of vascular endothelial growth factor (VEGF) from endothelial cells. The synergistic effect of histamine on VEGF production could be reversed by pretreatments with diphenhydramine (H1-receptor antagonist), SB203580 (selective p38 mitogen-activated protein kinase (MAPK) inhibitor) and L-NAME (nitric oxide synthase (NOS) inhibitor), but not with cimetidine (H2-receptor antagonist) and indomethacin (cyclooxygenase (COX) inhibitor). Moreover, histamine could augment bFGF-incuced phosphorylation and degradation of IκBα, a key factor accounting for the activation and translocation of nuclear factor κB (NF-κB) in endothelial cells. These findings indicated that histamine was able to synergistically augment bFGF-induced angiogenesis, and this action was linked to VEGF production through H1-receptor and the activation of endothelial nitric oxide synthase (eNOS), p38 MAPK, and IκBα in endothelial cells.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.forename: Xinghua
authors.initials: X
authors.lastname: Gao
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D016328:NF-kappa B; D011969:Receptors, Histamine H1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D006632:Histamine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D040262:Receptors, Vascular Endothelial Growth Factor; D020928:Mitogen-Activated Protein Kinases