BACKGROUND: We investigated the effects and possible mechanism of syngeneic bone marrow mononuclear cell (BM-MNC) transplantation on pulmonary arterial hypertension induced by monocrotaline. METHODS: Monocrotaline (80 mg/kg body weight) was administrated to C57BL/6 mice, and pulmonary arterial hypertension was induced 4 weeks later. Bone marrow mononuclear cells harvested from syngeneic donor mice were injected intravenously into those mice 4 weeks after monocrotaline administration. The ratio of right ventricular to septum plus left ventricular weight, the number of small pulmonary arteries, and medial thickness of pulmonary arteries were measured. Western immunoblotting of the lung tissue was performed to observe vascular endothelial growth factor and its receptor expression 1 week after BM-MNC transplantation. Vascular endothelial growth factor receptor-2 inhibitor was administered to pulmonary arterial hypertension mice simultaneously with BM-MNC transplantation. RESULTS: The ratio of right ventricular to septum plus left ventricular weight increased, the number of pulmonary arteries decreased, and medial thickness increased significantly 4 weeks after monocrotaline injection compared with those of vehicle-injected mice. These indices of monocrotaline-injected mice improved significantly 4 weeks after BM-MNC transplantation compared with those of mice at 8 weeks after monocrotaline injection (0.22 +/- 0.02 versus 0.31 +/- 0.02; 17.1 +/- 2.6 versus 8.2 +/- 1.7; 7.7% +/- 2.2% versus 20% +/- 2.1%, respectively; p < 0.01). However, BM-MNCs were not incorporated into the lung at 1 week after transplantation, and significant vascular endothelial growth factor upregulation and without receptor expression was observed in lung tissue 1 week after transplantation. Improvement of pulmonary arterial hypertension was inhibited by simultaneous administration of vascular endothelial growth factor receptor-2 inhibitor with BM-MNC transplantation. CONCLUSIONS: These results indicate that syngeneic BM-MNC transplantation improves monocrotaline-induced pulmonary arterial hypertension by favorable pulmonary artery remodeling through vascular endothelial growth factor upregulation.
BACKGROUND: We investigated the effects and possible mechanism of syngeneic bone marrow mononuclear cell (BM-MNC) transplantation on pulmonary arterial hypertension induced by monocrotaline. METHODS:Monocrotaline (80 mg/kg body weight) was administrated to C57BL/6 mice, and pulmonary arterial hypertension was induced 4 weeks later. Bone marrow mononuclear cells harvested from syngeneic donormice were injected intravenously into those mice 4 weeks after monocrotaline administration. The ratio of right ventricular to septum plus left ventricular weight, the number of small pulmonary arteries, and medial thickness of pulmonary arteries were measured. Western immunoblotting of the lung tissue was performed to observe vascular endothelial growth factor and its receptor expression 1 week after BM-MNC transplantation. Vascular endothelial growth factor receptor-2 inhibitor was administered to pulmonary arterial hypertensionmice simultaneously with BM-MNC transplantation. RESULTS: The ratio of right ventricular to septum plus left ventricular weight increased, the number of pulmonary arteries decreased, and medial thickness increased significantly 4 weeks after monocrotaline injection compared with those of vehicle-injected mice. These indices of monocrotaline-injected mice improved significantly 4 weeks after BM-MNC transplantation compared with those of mice at 8 weeks after monocrotaline injection (0.22 +/- 0.02 versus 0.31 +/- 0.02; 17.1 +/- 2.6 versus 8.2 +/- 1.7; 7.7% +/- 2.2% versus 20% +/- 2.1%, respectively; p < 0.01). However, BM-MNCs were not incorporated into the lung at 1 week after transplantation, and significant vascular endothelial growth factor upregulation and without receptor expression was observed in lung tissue 1 week after transplantation. Improvement of pulmonary arterial hypertension was inhibited by simultaneous administration of vascular endothelial growth factor receptor-2 inhibitor with BM-MNC transplantation. CONCLUSIONS: These results indicate that syngeneic BM-MNC transplantation improves monocrotaline-induced pulmonary arterial hypertension by favorable pulmonary artery remodeling through vascular endothelial growth factor upregulation.
Authors: Daniel J Weiss; Ivan Bertoncello; Zea Borok; Carla Kim; Angela Panoskaltsis-Mortari; Susan Reynolds; Mauricio Rojas; Barry Stripp; David Warburton; Darwin J Prockop Journal: Proc Am Thorac Soc Date: 2011-06