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Open Access Publications from the University of California

Interstitial Macrophage-Derived Thrombospondin-1 Contributes to Hypoxia-Induced Pulmonary Hypertension.

  • Author(s): Kumar, Rahul
  • Mickael, Claudia
  • Kassa, Biruk
  • Sanders, Linda
  • Hernandez-Saavedra, Daniel
  • Koyanagi, Daniel E
  • Kumar, Sushil
  • Pugliese, Steve C
  • Thomas, Stacey
  • McClendon, Jazalle
  • Maloney, James P
  • Janssen, William J
  • Stenmark, Kurt R
  • Tuder, Rubin M
  • Graham, Brian B
  • et al.

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AIMS:TGF-β signaling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-β by thrombospondin-1 (TSP-1) contributes to the pathogenesis of hypoxia-induced PH. However, neither the cellular source of pathologic TSP-1 nor the downstream signaling pathway that link activated TGF-β to PH have been determined. In this study, we hypothesized that circulating monocytes, which are recruited to become interstitial macrophages, are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho kinase signaling, causing vasoconstriction. METHODS AND RESULTS:Flow cytometry revealed that a specific subset of interstitial macrophages is the major source of pathologic TSP-1 in hypoxia. Intravenous depletion and parabiosis experiments demonstrated that these cells are circulating prior to recruitment into the interstitium. Rho kinase mediated vasoconstriction was a major downstream target of active TGF-β. Thbs1 deficient bone marrow protected against hypoxic-PH by blocking TGF-β activation and Rho kinase-mediated vasoconstriction. CONCLUSIONS:In hypoxia-challenged mice, bone marrow derived and circulating monocytes are recruited to become interstitial macrophages which express TSP-1, resulting in TGF-β activation and Rho kinase-mediated vasoconstriction. TRANSLATIONAL PERSPECTIVES:Inflammation contributes to the pathogenesis of many forms of pulmonary hypertension, but blocking inflammation has not been a successful therapeutic strategy to date. Here we found that mice with experimental hypoxia-induced pulmonary hypertension have recruitment of circulating, classical monocytes into the lungs, and that these cells express the protein thrombospondin-1 that causes activation of TGF-β and results in Rho-kinase mediated vasoconstriction. These data suggest that more precise targeting of inflammation, such as blocking specific cells like monocytes or cytokines like TGF-β, would be a more effective future therapeutic approach for pulmonary hypertension etiologies where these pathways underlie disease pathogenesis.

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This item is under embargo until November 26, 2020.