Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension

Cardiovasc Res. 2020 Oct 1;116(12):2021-2030. doi: 10.1093/cvr/cvz304.

Abstract

Aims: 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.

Conclusion: 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.

Keywords: Inflammation; Interstitial macrophages; Pulmonary hypertension; Vasoconstriction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blood Pressure
  • Disease Models, Animal
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / prevention & control
  • Hypoxia / complications*
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Parabiosis
  • Signal Transduction
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Transforming Growth Factor beta1 / metabolism
  • Vasoconstriction*
  • rho-Associated Kinases / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Tgfb1 protein, mouse
  • Thrombospondin 1
  • Transforming Growth Factor beta1
  • Thbs1 protein, mouse
  • endothelial PAS domain-containing protein 1
  • rho-Associated Kinases