Benzo[a]pyrene inhibits angiogenic factors-induced alphavbeta3 integrin expression, neovasculogenesis, and angiogenesis in human umbilical vein endothelial cells.
New blood vessel formation is necessary for the repair of ischemia-damaged tissues. Endothelial cells produce exogenous and endogenous angiogenic factors in the mediation of angiogenesis and neovasculogenesis during neovascularization. Exposure to environmental pollutants may alter proangiogenic capacity or desensitize the responses of endothelial cells to stimulation by basic fibroblast growth factor and vascular endothelial growth factor. Human umbilical vein endothelial cells (HUVECs) were pretreated with benzo[a]pyrene (B[a]P), the major carcinogenic constituent found in tobacco smoke, for 24 h. Neovasculogenesis, migration, and proliferation were evaluated in solvent-treated and B[a]P-treated HUVECs. Endothelial capillary-like tube formation, cell migration, mitogen-activated protein kinase (MAPK) phosphorylation, and integrin expression were reduced in B[a]P-treated HUVECs with angiogenic factor stimulation, in comparison to solvent-treated HUVECs, although cell proliferation and Akt activation remained unaffected. Inhibition of B[a]P-mediated MAPK and neovasculogenesis was significantly rescued by pretreatment with α-naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist. The B[a]P-mediated inhibition of neovasculogenesis was also rescued in AhR-silenced HUVECs, suggesting the requirement for AhR in B[a]P-associated effects. B[a]P also inhibited angiogenesis in a chorioallantoic membrane assay. We conclude that B[a]P is a potent inhibitor of angiogenesis, and its effects are mediated via AhR-dependent phenotypic changes in B[a]P-treated HUVECs. These findings contribute to an understanding of the involvement of AhR agonists in vasculotoxicity.
Li
Ching-Hao
CH
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Cheng
Yu-Wen
YW
Hsu
Yao-Teng
YT
Hsu
Yu-Jeng
YJ
Liao
Po-Ling
PL
Kang
Jaw-Jou
JJ
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D014471:Umbilical Veins / Q000166:cytology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002273:Carcinogens; D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D001564:Benzo(a)pyrene; D019324:beta-Naphthoflavone; D020928:Mitogen-Activated Protein Kinases