Skip to main content
eScholarship
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.

Published Web Location

https://doi.org/10.1093/cvr/cvz304
No data is associated with this publication.
Abstract

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content

This item is under embargo until November 26, 2020.