title: Hypoxia enhances platelet-derived growth factor signaling in the pulmonary vasculature by down-regulation of protein tyrosine phosphatases.
abstract: BACKGROUND
  Platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of pulmonary hypertension (PH) because it promotes pulmonary vascular remodeling. PH is frequently associated with pulmonary hypoxia.
  
  
  OBJECTIVE
  To investigate whether hypoxia alters PDGF β receptor (βPDGFR) signaling in the pulmonary vasculature.
  
  
  METHODS
  The impact of chronic hypoxia on signal transduction by the βPDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo.
  
  
  RESULTS
  Chronic hypoxia significantly enhanced PDGF-BB-dependent proliferation and chemotaxis of hPASMC. Pharmacologic inhibition of PI3 kinase (PI3K) and PLCγ abrogated these events under both normoxia and hypoxia. Although hypoxia did not affect βPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLCγ (Y1021). The activated βPDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Interestingly, hypoxia decreased expression of numerous PTPs (T cell PTP, density-enhanced phosphatase-1, PTP1B, and SH2 domain-containing phosphatase-2), resulting in reduced PTP activity. Hypoxia-inducible factor (HIF)-1α is involved in this regulation of gene expression, because hypoxia-induced βPDGFR hyperphosphorylation and PTP down-regulation were abolished by HIF-1α siRNA and by the HIF-1α inhibitor 2-methoxyestradiol. βPDGFR hyperphosphorylation and PTP down-regulation were also present in vivo in mice with chronic hypoxia-induced PH.
  
  
  CONCLUSIONS
  Hypoxia reduces expression and activity of βPDGFR-antagonizing PTPs in a HIF-1α-dependent manner, thereby enhancing receptor activation and proliferation and chemotaxis of hPASMC. Because hyperphosphorylation of the βPDGFR and down-regulation of PTPs occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other hypoxia-associated diseases.
authors.affiliation: Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Kerpener Strasse 62, Köln, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: ten Freyhaus
authors.forename: Markus
authors.initials: M
authors.lastname: Dagnell
authors.forename: Maike
authors.initials: M
authors.lastname: Leuchs
authors.forename: Marius
authors.initials: M
authors.lastname: Vantler
authors.forename: Eva M
authors.initials: EM
authors.lastname: Berghausen
authors.forename: Evren
authors.initials: E
authors.lastname: Caglayan
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011651:Pulmonary Artery / Q000503:physiopathology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D017027:Protein Tyrosine Phosphatases