title: Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension.
abstract: BACKGROUND
  Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process.
  
  
  OBJECTIVE
  To determine whether progenitors are involved in the pathobiology of PAH.
  
  
  METHODS
  We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. measurements and main results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of late-outgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks.
  
  
  CONCLUSIONS
  These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process.
authors.affiliation: Papworth Hospital, Cambridge, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Toshner
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Rafia
authors.initials: R
authors.lastname: Al-Lamki
authors.forename: Luke S G
authors.initials: LS
authors.lastname: Howard
authors.forename: Denis
authors.initials: D
authors.lastname: Marchesan
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jay
authors.initials: J
authors.lastname: Suntharalingam
authors.forename: Elaine
authors.initials: E
authors.lastname: Soon
authors.forename: Andrew
authors.initials: A
authors.lastname: Exley
authors.forename: Susan
authors.initials: S
authors.lastname: Stewart
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Ursula
authors.initials: U
authors.lastname: Gehling
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Joanna
authors.initials: J
authors.lastname: Pepke-Zaba
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000502:physiology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011651:Pulmonary Artery; D013234:Stem Cells / Q000502:physiology
chemical_list: D052006:Bone Morphogenetic Protein Receptors, Type II