title: Upregulation of a disintegrin and metalloproteinase-33 by VEGF in human airway smooth muscle cells: Implications for asthma.
abstract: Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling. Features of airway remodeling include increased airway smooth muscle (ASM) mass. A disintegrin and metalloproteinase (ADAM)-33 has been identified as playing a role in the pathophysiology of asthma. ADAM-33 is expressed in ASM cells and is suggested to play a role in the function of these cells. However, the regulation of ADAM-33 is not fully understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Although VEGF was initially thought of as an endothelial-specific growth factor, recent reports have found that VEGF can promote proliferation of other cell types, including ASM cells. To investigate the precise mechanism of VEGF's effect on ASM cell proliferation, we tested the expression of ADAM-33, phospho-extracellularsignal-regulated kinase 1/2 (ERK1/2), and phospho-Akt in VEGF-stimulated ASM cells. We found that VEGF up-regulates ADAM-33 mRNA and protein levels in a dose- and time-dependent manner as well as phosphorylation of ERK1/2 and Akt. We also found that VEGF-induced ASM cell proliferation is inhibited by both ADAM-33 knockdown and a selective VEGF receptor 2 (VEGFR2) inhibitor (SU1498). Furthermore, VEGF-induced ADAM-33 expression and ASM cell proliferation were suppressed by inhibiting ERK1/2 activity, but not by inhibiting Akt activity. Collectively, our findings suggest that VEGF enhances ADAM-33 expression and ASM cell proliferation by activating the VEGFR2/ERK1/2 signaling pathway, which might be involved in the pathogenesis of airway remodeling. Further elucidation of the mechanisms underlying these observations might help develop therapeutic strategies for airway diseases associated with smooth muscle hyperplasia such as asthma.
authors: a Department of Radiology , Tianjin Hospital of Integrated Traditional Chinese and Western Medicine , Tianjin , China.
authors: Qing-Mei
authors: QM
authors: Pei
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Ping
authors: P
authors: Jiang
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Min
authors: M
authors: Yang
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Xue-Jiao
authors: XJ
authors: Qian
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Jiang-Bo
authors: JB
authors: Liu
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Hong
authors: H
authors: Zheng
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Li-Hong
authors: LH
authors: Zhao
authors: b Department of Respiration , Tianjin First Central Hospital , Tianjin , China.
authors: Sung-Ho
authors: SH
authors: Kim
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D002934:Cinnamates / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D002070:Butadienes; D002934:Cinnamates; D009570:Nitriles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C483044:SU 1498; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; C450441:ADAM33 protein, human
keywords: ADAM-33; Akt; ERK1/2; VEGF; airway remodeling