Bosentan Promotes Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells but Inhibits Infiltration of Macrophages into Pulmonary Vascular Lesions in Mice: A New Mechanism of Bosentan in Inhibiting Pulmonary Hypertension

  • Dr Taichi Kato, Mie University Graduate School of Medicine, Japan
  • Dr Yoshihide Mitani, Mie University Graduate School of Medicine, Japan
  • Junko Maruyama, Mie University Graduate School of Medicine, Japan
  • Dr Hiroyuki Ohashi, Mie University Graduate School of Medicine, Japan
  • Masahiro Masuya, Mie University Graduate School of Medicine, Japan
  • Prof Hideto Shimpo, Mie University Graduate School of Medicine, Japan
  • Kazuo Maruyama, Mie University Graduate School of Medicine, Japan
  • Dr Yoshihiro Komada, Mie University Graduate School of Medicine, Japan

    • Background: Recent studies demonstrated that administration of endothelial progenitor cells (EPCs) or suppression of several inflammatory pathways inhibited the development of pulmonary hypertension (PH) in animals. We tested the hypothesis that bosentan modulates the incorporation of bone marrow (BM)-derived EPCs and macrophages into pulmonary vascular lesions. Methods and Results: Lethally irradiated C57BL6 mice, transplanted with BM cells from littermates expressing eGFP, were kept in hypobaric hypoxia (380mmHg) or in the ambient air, and were injected with saline or bosentan sodium salt (30mg/kg/d, ip), for 21 days. Compared with controls (17.6±0.9mmHg), right ventricular systolic pressure was increased in hypoxic mice (26.6±1.0, p<.05), which was inhibited by bosentan (22.9±1.1, p<.05). Furthermore, compared with controls, percentages of CD31+eGFP+BM-derived endothelial cells/ whole CD31+ cells (4.3±0.3 vs 1.4±0.1) and of MOMA2+eGFP+BM-derived macrophages/ whole MOMA2+ cells (38.4±5.5 vs 17.4±2.6) were higher in hypoxic mice (p<.05), either of which were promoted (5.5±0.3) or inhibited (18.6±2.4) by bosentan (p<.05), respectively. Consistently, compared with controls, percentages of EPCs/ whole mononuclear cells in the peripheral blood were increased in hypoxic mice, which were further increased by bosentan. Conclusions: Bosentan promoted BM-derived EPC incorporation but inhibited macrophage infiltration into pulmonary vascular lesions. Modulation of BM-derived cells could be a new mechanism of bosentan in inhibiting PH.