title: Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension.
abstract: BACKGROUND
  Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries.
  
  
  OBJECTIVE
  To analyze the expression and pathogenic role of PDGF in idiopathic PAH.
  
  
  METHODS
  PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-beta. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs.
  
  
  RESULTS
  PDGF-A, PDGF-B, PDGFR-alpha, and PDGFR-beta mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-beta in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-alpha and PDGFR-beta mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-beta. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis.
  
  
  CONCLUSIONS
  PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.
authors.affiliation: Centre National de Référence de l'Hypertension Artérielle Pulmonaire, Service de Pneumologie et Réanimation Respiratoire, Institut Paris-Sud Cytokines, Hôpital Antoine-Béclère, Université Paris-Sud 11, UPRES EA 2705, Clamart, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Ingrid
authors.initials: I
authors.lastname: Durand-Gasselin
authors.forename: Colas
authors.initials: C
authors.lastname: Tcherakian
authors.forename: Jérôme
authors.initials: J
authors.lastname: Le Pavec
authors.forename: Michel
authors.initials: M
authors.lastname: Mazmanian
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Sacha
authors.initials: S
authors.lastname: Mussot
authors.forename: Olaf
authors.initials: O
authors.lastname: Mercier
authors.forename: Philippe
authors.initials: P
authors.lastname: Hervé
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Rogério
authors.initials: R
authors.lastname: Souza
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001549:Benzamides; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D000068877:Imatinib Mesylate; D008168:Lung / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism
chemical_list: D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor