Abstract 3628: Bosentan Promotes Incorporation of Bone Marrow-derived Endothelial Cells but Inhibited Infiltration of Macrophages Into Pulmonary Vascular Lesions in Mice Exposed to Chronic Hypoxia: A Novel Concept of Bosentan Therapy in Pulmonary Hypertension
Background: Bone marrow (BM)-derived vascular cells, together with resident cells, were reported to mediate the development of various vascular diseases. We therefore tested the hypothesis that an efficacious pulmonary vasodilator bosentan modulates the kinetics of bone marrow stem cells, in inhibiting the development of pulmonary vascular lesions in mice exposed to chronic hypoxia.
Methods: BM chimeric mice (n=54) were produced after being lethally irradiated and transplanted with BM cells (2x 106) from littermates expressing enhanced green fluorescent protein (eGFP). These animals, exposed to hypobaric hypoxia (380mmHg) or kept in the ambient air, were injected with saline or bosentan sodium salt (30mg/kg/d, ip) for 21 days. After the treatment period, right ventricular systolic pressure (RVSP) was measured and pulmonary vascular morphometry was conducted. Tissue sections were immunostained and analyzed by using laser scanning confocal microscopy, quantitatively.
Results: Compared with control mice, RVSP (26.6±1.0 vs 17.6±.9mmHg, p<.05) and the right to left ventricle weight ratio (RV/LV) (.42±.07 vs .27±.04, p<.05) were increased in saline-treated hypoxic mice, which were inhibited by bosentan (22.9±1.1mmHg, p<.05; .35±.04, p<.05). Consistently, compared with control mice, percentages of muscularized vessels were increased in saline-treated hypoxic mice (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 inhibited by bosentan (68.4±1.4%, p<.05; 59.5±3.8%, p<.05). Interestingly, compared with controls, percentages of CD31+eGFP+BM-derived endothelial cells/whole CD31+cells (4.3±.3 vs 1.4±.1%, p<.05) and of MOMA2+eGFP+BM-derived macrophages/whole MOMA2+cells (38.4±5.5 vs 17.4±2.6%, p<.05) were higher in hypoxic mice, either of which was promoted (5.5±.3, p<.05) or inhibited (18.6±2.4, p<.05) by bosentan.
Conclusions: Bosentan promoted the engraftment of BM derived-endothelial cells but inhibited BM-derived macrophage infiltration into pulmonary vascular lesions in mice exposed to chronic hypoxia, in inhibiting pulmonary hypertension (PH). Pharmacomodulation of BM-derived cells could be a novel concept of medical treatment against PH.