title: The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: implications for airway remodeling in asthma.
abstract: BACKGROUND
  A disintegrin and metalloprotease (ADAM)-33 is a susceptibility gene for asthma and chronic obstructive pulmonary disease whose function remains unknown.
  
  
  OBJECTIVE
  Because asthmatic bronchoalveolar lavage fluid contains high levels of soluble ADAM33 (sADAM33), which includes the catalytic domain, we postulated that its release from cell membranes might play functional roles in airway remodeling by promoting angiogenesis.
  
  
  METHODS
  The proangiogenic activity of the highly purified catalytic domain of ADAM33 or a catalytically inactive mutant was studied in vitro (Matrigel assay), ex vivo (human embryonic/fetal lung explants) and in vivo (chorioallantoic membrane assay). The regulation of sADAM33 release from cells overexpressing full-length ADAM33 and its biological activity were characterized.
  
  
  RESULTS
  We show that the purified catalytic domain of ADAM33, but not its inactive mutant, causes rapid induction of endothelial cell differentiation in vitro, and neovascularization ex vivo and in vivo. We also show that TGF-beta(2) enhances sADAM33 release from cells overexpressing full-length ADAM33 and that this truncated form is biologically active.
  
  
  CONCLUSIONS
  The discovery that sADAM33 promotes angiogenesis defines it as a tissue remodeling gene with potential to affect airflow obstruction and lung function independently of inflammation. As TGF-beta(2) enhances sADAM33 release, environmental factors that cause epithelial damage may synergize with ADAM33 in asthma pathogenesis, resulting in a disease-related gain of function. This highlights the potential for interplay between genetic and environmental factors in this complex disease.
authors.affiliation: Division of Infection, Inflammation, and Repair, School of Medicine, Southampton General Hospital, University of Southampton, Southampton, United Kingdom.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Puxeddu
authors.forename: Yun Yun
authors.initials: YY
authors.lastname: Pang
authors.forename: Anna
authors.initials: A
authors.lastname: Harvey
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Ben
authors.initials: B
authors.lastname: Nicholas
authors.forename: Hajime
authors.initials: H
authors.lastname: Yoshisue
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Geraldine
authors.initials: G
authors.lastname: Clough
authors.forename: Rob M
authors.initials: RM
authors.lastname: Powell
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020134:Catalytic Domain / Q000502:physiology*; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D051722:ADAM Proteins; C450441:ADAM33 protein, human