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

ABSTRACT: AIMS:Transforming growth factor-? (TGF-?) signalling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-? 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-? 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-? 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-?. Thbs1 deficient bone marrow (BM) protected against hypoxic-PH by blocking TGF-? 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-? activation and Rho-kinase-mediated vasoconstriction.

SUBMITTER: Kumar R 

PROVIDER: S-EPMC7519884 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature