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

Abstract

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