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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 559584.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Hypoxia Enhances PDGF Signaling in the Pulmonary Vasculature by Downregulation of Protein Tyrosine Phosphatases
Authors:Ten Freyhaus, H.; Dagnell, M.; Leuchs, M.; Vantler, M.; Berghausen, E.; Caglayan, E.; Weissmann, N.; Dahal, B. K.; Schermuly, R. T.; Ostman, A.; Kappert, K.; Rosenkranz, S.
Title of Journal:Am J Respir Crit Care Med
Audience:Not Specified
Abstract / Description:RATIONALE: Platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of pulmonary hypertension (PH) as it promotes pulmonary vascular remodeling. PH is frequently associated with pulmonary hypoxia. OBJECTIVE: To investigate whether hypoxia alters PDGF beta receptor (betaPDGFR) signaling in the pulmonary vasculature. METHODS: The impact of chronic hypoxia on signal transduction by the betaPDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo. MEASUREMENTS AND MAIN RESULTS: Chronic hypoxia significantly enhanced PDGF-BB-dependent proliferation and chemotaxis of hPASMC. Pharmacological inhibition of PI3 kinase (PI3K) and PLCgamma abrogated these events under both normoxia and hypoxia. While hypoxia did not affect betaPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLCgamma (Y1021). The activated betaPDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Interestingly, hypoxia decreased expression of numerous PTPs (TC-PTP, DEP-1, PTP1B, SHP-2), resulting in reduced PTP activity. HIF-1alpha is involved in this regulation of gene expression, as hypoxia-induced betaPDGFR hyperphosphorylation and PTP downregulation were abolished by HIF-1alpha siRNA and by the HIF-1alpha inhibitor 2-methoxyestradiol. betaPDGFR hyperphosphorylation and PTP downregulation were also present in vivo in mice with chronic hypoxia-induced PH. CONCLUSIONS: Hypoxia reduces expression and activity of betaPDGFR-antagonizing PTPs in a HIF-1alpha-dependent manner, thereby enhancing receptor activation and proliferation/chemotaxis of hPASMC. As hyperphosphorylation of the betaPDGFR and downregulation of PTPs occur in vivo, this mechanism likely has significant impact on development and progression of PH and other hypoxia-associated diseases.
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:University of Cologne, Cologne, Germany.
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking)
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