Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension. Issue 12 (9th November 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cardiovascular research. Volume 116:Issue 12(2020)
• Page Start: 2021
• Page End: 2030
• Publication Date: 2019-11-09
• Subjects: Pulmonary hypertension -- Vasoconstriction -- Interstitial macrophages -- Inflammation; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz304
• Languages: English
• ISSNs: 0008-6363

Abstract

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. Graphical Abstract: