| First Author | Kumar R | Year | 2020 |
| Journal | Cardiovasc Res | Volume | 116 |
| Issue | 12 | Pages | 2021-2030 |
| PubMed ID | 31710666 | Mgi Jnum | J:313804 |
| Mgi Id | MGI:6707501 | Doi | 10.1093/cvr/cvz304 |
| Citation | Kumar R, et al. (2020) Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension. Cardiovasc Res 116(12):2021-2030 |
| abstractText | 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. Thbs1 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. |
