Abstract 13096: Role of Endogenous Bone Marrow-Derived Stem Cells and Its Pharmacological Modulation in Pulmonary Arterial Hypertension in Mice: A New Mechanism of Action in Bosentan Therapy
Background: Bone marrow(BM)-derived stem cells were reported to play an important role in various physiological and pathological conditions of vessels. We investigated whether endothelin receptor antagonist bosentan modulates the kinetics of BM-derived stem cells in inhibiting the development of pulmonary vascular disease (PVD) in mice, and the mechanisms involved.
Methods: BM chimeric mice, which were transplanted with eGFP-positive BM mononuclear cells after lethal irradiation, were exposed to hypobaric hypoxia for 21 days or kept in the ambient air, and were daily treated with bosentan sodium salt (30mg/kg/d, ip) or saline for 21 days. After the treatment period, right ventricular pressure was measured and morphometry of the lung tissue was conducted. Incorporation of BM-derived cells were analyzed by immunohistochemistry. Gene expression of SDF1, VEGF, PlGF, MCP1, HGF, IL6 and ET-1 in the lung tissue was evaluated by quantitative real time PCR (RT-PCR).
Results: In mice exposed to hypoxia, pulmonary hypertension (PH) (26.6±1.0 vs 17.6±0.9mmHg, p<.05) and the percentage of muscularized vessel were increased(82.9±2.7 vs 47.2±1.2% in the alveolar duct level, p<.05; 75.0±3.2 vs 36.1±2.9% in the alveolar wall level, p<.05), which were ameliorated by bosentan (22.9±1.1mmHg, p<.05; 68.4±1.4%, p<.05; 59.5±3.8%, p<.05). Immunohistochemical analysis demonstrated that BM-derived endothelial cells (ECs) (4.3±0.3% vs 1.4±0.1%, p<.05) and BM-derived macrophages (38.4±5.5% vs 17.4±2.6%, p<.05) were increased in lungs of PH mice compared with controls. Bosentan promoted BM-derived EC incorporation(5.5±0.3%, p<.05) but inhibited macrophage infiltration(18.6±2.4%, p<.05) into PVD. Quantitative RT-PCR analysis revealed that SDF1, VEGF, PlGF, MCP1, HGF, IL6 and ET-1 were upregulated in lungs of PH mice compared with control mice (p<.05). In addition, bosentan upregulated SDF1(p<.05) but downregulated MCP1(p<.05) and IL6(p<.05) compared with PH mice without treatment.
Conclusions: Bosentan ameliorates PH by specifically modulating the kinetics of BM-derived stem cells and the related gene expression, which could be a novel therapeutic target in inhibiting PH.
- © 2012 by American Heart Association, Inc.