BACKGROUND Airway mucus hypersecretion is an important pathophysiological feature in asthma. Mucins are glycoproteins that are mainly responsible for the viscoelastic property of mucus, and MUC5AC is a major mucin glycoprotein that is overproduced in asthma. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Therefore, we sought to investigate the effect of VEGF on MUC5AC expression and study the underlying mechanisms. METHODS In order to elucidate the precise mechanism underlying the effect of VEGF on MUC5AC expression, we tested the effects of VEGF on RhoA activation and the association of caveolin-1 and VEGFR2 in Primary Bronchial Epithelial Cells. RESULTS VEGF up-regulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and activated RhoA. Additionally, VEGF-induced MUC5AC expression and RhoA activation were enhanced by disrupting caveolae with cholesterol depletion and reversed by cholesterol repletion, and inhibited by a selective VEGF receptor 2 (VEGFR2) inhibitor SU1498. Furthermore, phospho-VEGFR2 expression was decreased via overexpression of caveolin-1. VEGF treatment reduced the association of caveolin-1 and VEGFR2. CONCLUSION Collectively, our findings suggest that VEGF up-regulates MUC5AC expression and RhoA activation by interaction with VEGFR2, and this phenomenon was related with the association of caveolin-1 and VEGFR2. Further studies on these mechanisms are needed to facilitate the development of treatments for asthma.

中文翻译：

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VEGF在人原代支气管上皮细胞中对MUC5AC的上调：对哮喘的影响。

背景技术气道粘液分泌过多是哮喘的重要病理生理特征。粘蛋白是主要负责粘液粘弹性质的糖蛋白，而MUC5AC是哮喘中过量产生的主要粘蛋白糖蛋白。血管内皮生长因子（VEGF）与哮喘患者的炎症和气道血管重塑有关。因此，我们试图研究VEGF对MUC5AC表达的影响并研究其潜在机制。方法为了阐明VEGF对MUC5AC表达的影响的确切机制，我们测试了VEGF对RhoA活化的影响以及原代支气管上皮细胞中Caveolin-1和VEGFR2的关联。结果VEGF以剂量和时间依赖性方式上调MUC5AC mRNA和蛋白水平，并激活RhoA。此外，VEGF诱导的MUC5AC表达和RhoA活化可通过破坏胆固醇消耗的小窝而增强，并被胆固醇补充所逆转，并被选择性VEGF受体2（VEGFR2）抑制剂SU1498抑制。此外，磷酸-VEGFR2的表达通过caveolin-1的过表达而降低。VEGF治疗降低了caveolin-1和VEGFR2的关联。结论综上所述，我们的发现提示VEGF通过与VEGFR2相互作用上调了MUC5AC表达和RhoA激活，并且这种现象与Caveolin-1和VEGFR2的关联有关。需要进一步研究这些机制，以促进哮喘治疗的发展。VEGF诱导的MUC5AC表达和RhoA激活通过破坏胆固醇消耗的小窝而增强，并被胆固醇补充所逆转，并被选择性VEGF受体2（VEGFR2）抑制剂SU1498抑制。此外，磷酸-VEGFR2的表达通过caveolin-1的过表达而降低。VEGF治疗降低了caveolin-1和VEGFR2的关联。结论综上所述，我们的发现提示VEGF通过与VEGFR2相互作用上调了MUC5AC表达和RhoA激活，并且这种现象与Caveolin-1和VEGFR2的关联有关。需要进一步研究这些机制，以促进哮喘治疗的发展。VEGF诱导的MUC5AC表达和RhoA激活通过破坏胆固醇消耗的小窝而增强，并被胆固醇补充所逆转，并被选择性VEGF受体2（VEGFR2）抑制剂SU1498抑制。此外，磷酸-VEGFR2的表达通过caveolin-1的过表达而降低。VEGF治疗降低了caveolin-1和VEGFR2的关联。结论综上所述，我们的发现提示VEGF通过与VEGFR2相互作用上调了MUC5AC表达和RhoA激活，并且这种现象与Caveolin-1和VEGFR2的关联有关。需要进一步研究这些机制，以促进哮喘治疗的发展。磷酸-VEGFR2的表达通过caveolin-1的过表达而降低。VEGF治疗降低了caveolin-1和VEGFR2的关联。结论综上所述，我们的发现提示VEGF通过与VEGFR2相互作用上调了MUC5AC表达和RhoA激活，并且这种现象与Caveolin-1和VEGFR2的关联有关。需要进一步研究这些机制，以促进哮喘治疗的发展。磷酸-VEGFR2的表达通过caveolin-1的过表达而降低。VEGF治疗降低了caveolin-1和VEGFR2的关联。结论综上所述，我们的发现提示VEGF通过与VEGFR2相互作用上调了MUC5AC表达和RhoA激活，并且这种现象与Caveolin-1和VEGFR2的关联有关。需要进一步研究这些机制，以促进哮喘治疗的发展。