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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.


Transforming growth factor-β (TGF-β) signalling 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 signalling 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 (IMs), are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho-kinase signalling, causing vasoconstriction.

Methods and results

Flow cytometry revealed that a specific subset of IMs 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 (BM) protected against hypoxic-PH by blocking TGF-β activation and Rho-kinase-mediated vasoconstriction.


In hypoxia-challenged mice, BM derived and circulating monocytes are recruited to become IMs which express TSP-1, resulting in TGF-β activation and Rho-kinase-mediated vasoconstriction.

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