| Summary: | 碩士 === 國立臺灣大學 === 毒理學研究所 === 95 === Smoking induces many pathologic changes in the blood vessel wall, including endothelial cell injury, an event that is critical in the pathogenesis of vascular disease. It has been reported that polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are strongly involved in the pathogenesis of cardiovascular diseases such as cardiomyopathy, ischemic heart diseases, heart failure, myocardial infarction, hypertension, and atherosclerosis. Angiogenesis, the process by which new blood vessels develop from pre-existing blood vessels, impacts significantly on many important disease states including cancer and ischemic cardiovascular disease. Recent studies have been show cigarette smoke exposure can impair angiogenesis. The PAH-benzo[a]pyrene is one smoke-related compound that has been associated with endothelial damage in blood vessels, and it has also been reported that B[a]P concentration is as high as 10-50 ng per cigarette. Thus, the results of these studies promote us to investigate the effects of B[a]P on angiogenesis. In this study, we found that in vitro tube formation of HUVECs was affected by pretreatment with B[a]P in various concentrations ( 0.33~10μM ) for 24 hr and basic fibroblast growth factor ( bFGF )-/ vascular endothelial growth factor ( VEGF )-induced tube formation was inhibited dose-dependently in B[a]P pretreated HUVECs. B[a]P also inhibited the bFGF-/VEGF-induced chemotactic motility in cell migration assay. Taken together, B[a]P can inhibit angiogenesis in an in vitro system and this antiangiogenic activity might be due to the inhibition of endothelial cell migration.
Angiogenesis is regulated by signals derived from receptors for both growth factors and ECM molecules. Recent studies have shown that activation of ERKs is closely involved in the migration or tubular-like formation of endothelial cells and induced by various angiogenic factors. Therefore, we want further to investigate effects of B[a]P on HUVECs ERK activation and cell surface integrin αvβ3 expression. We found bFGF-/VEGF-induced ERK activation and bFGF-induced cell surface integrin αvβ3 expression were suppressed in B[a]P pretreated HUVECs. Interestingly, the inhibition of bFGF-induced ERK activation by B[a]P was eliminated to a greater extent by aryl hydrocarbon receptor( AhR ) antagonists, alpha-naphthoflavon ( alpha-NF ). Therefore, we thought that AhR might involved in inhibition of growth factor-induced ERK activation by B[a]P. In conclusion, these results indicate that the in vitro inhibition of B[a]P on endothelial cell angiogenesis might be due to suppression of mitogen-activated protein kinase ERK-dependent pathway and cell surface integrin αvβ3 expression, and then further suppresses endothelial cell migration.
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