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

Abstract

Aims TGF-β signaling 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 signaling 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, are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho kinase signaling, causing vasoconstriction. Methods and Results Flow cytometry revealed that a specific subset of interstitial macrophages 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 protected against hypoxic-PH by blocking TGF-β activation and Rho kinase-mediated vasoconstriction. Conclusions In hypoxia-challenged mice, bone marrow derived and circulating monocytes are recruited to become interstitial macrophages which express TSP-1, resulting in TGF-β activation and Rho kinase-mediated vasoconstriction. Translational Perspectives Inflammation contributes to the pathogenesis of many forms of pulmonary hypertension, but blocking inflammation has not been a successful therapeutic strategy to date. Here we found that mice with experimental hypoxia-induced pulmonary hypertension have recruitment of circulating, classical monocytes into the lungs, and that these cells express the protein thrombospondin-1 that causes activation of TGF-β and results in Rho-kinase mediated vasoconstriction. These data suggest that more precise targeting of inflammation, such as blocking specific cells like monocytes or cytokines like TGF-β, would be a more effective future therapeutic approach for pulmonary hypertension etiologies where these pathways underlie disease pathogenesis.

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

“…Indeed, expression of CCR2 and CCL5-CCR5 was needed in both macrophages and PASMCs to initiate and amplify PASMC proliferation [33]. When circulating monocytes differentiate into interstitial macrophages in hypoxia-induced PH in mice, they express thrombospondin-1 (TSP-1), leading to Rho kinase-mediated vasoconstriction through transforming growth factor beta (TGF-β) activation [34], thereby amplifying PH pathology. All these studies suggest a potentially crucial role for chemokine-mediated macrophage recruitment in the early pathogenesis of PH.…”

Schistosomiasis Pulmonary Arterial Hypertension

“…Many studies have started to dissect the immunological events that underlie SchPH pathogenesis (1,61,87,89,92,96,97,(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114). The current understanding of the signaling events is summarized in Figure 6.…”

“…The necessity of this pathway is demonstrated by protection from SchPH by blocking TGF-b signaling through techniques such as neutralizing antibodies, TGF-b receptor inhibitors, and Smad3 deficiency (109). TGF-b signaling can also contribute to vasoconstriction through noncanonical signaling such as RhoA/Rho-kinase, which is also observed in SchPH mice (109,113).…”

“…Overall, the Schistosoma model system seems highly pertinent to understanding the signaling axis between Th2 inflammation, TGF-b signaling and pulmonary vascular disease that connects Schistosoma exposure to the subsequent development of SchPH. Some of these mechanisms are shared with other PH models, as blocking TGF-b signaling is also protective in hypoxia-exposed mice and monocrotaline-exposed rats (109,113,124,125): TGF-b signaling may represent a final common pathway in PH pathogenesis, which is activated by different routes such as Type 2 inflammation activating TSP-1 in schistosomiasis.…”

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

“…A potential explanation arises from the notion that secreted factors from leukocytes have mitogenic, chemotactic and vasoconstrictive effects, including IL-6 [ 37 ], platelet-derived growth factor (PDGF) [ 38 , 45 ] and endothelin (ET)-1 [ 13 ]. Many of these factors are secreted by macrophages that are causally linked to PAH disease progression [ 26 , 48 ].…”