Interstitial Macrophage-Derived Thrombospondin-1 Contributes to Hypoxia-Induced Pulmonary Hypertension.

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