Autologous transplantation of bone marrow-derived endothelial progenitor cells attenuates monocrotaline-induced pulmonary arterial hypertension in rats

Abstract

Objectives: Bone marrow-derived endothelial progenitor cells have been shown to circulate to damaged vascular endothelium and differentiate into mature endothelial cells. This study investigated whether bone marrow-derived endothelial progenitor cell therapy ameliorates monocrotaline (MCT)-induced pulmonary arterial hypertension in a rat model.

Design: Male Sprague-Dawley rats were randomized to receive MCT (75 mg/kg) only (group 1), MCT plus autologous bone marrow-derived endothelial progenitor cell (1.2 x 10(6) cells) transplantation (group 2), and saline injection only (group 3). Mononuclear cells were obtained from femoral bone marrow of group 2 rats and isolated by Ficoll gradient centrifugation. The cells were cultured for 21 days in endothelial culture medium.

Setting: An animal research laboratory at Kaohsiung Chang Gung Memorial Hospital.

Measurements: Hemodynamics, ventricular weight, expressions of connexin43, endothelial nitric oxide synthase messenger RNA gene, Bcl-2, and number of alveolar sacs and small lung arterioles were measured.

Results: Hemodynamic measurements on day 28 after MCT treatment revealed the development of significantly increased pulmonary arterial hypertension in MCT-treated groups (p < .0001). The bone marrow-derived endothelial progenitor cells were intravenously transplanted in group 2 on day 28 after MCT-induced pulmonary arterial hypertension. By day 90 after MCT treatment, the right ventricular systolic blood pressure and right ventricular hypertrophy were significantly increased in group 1 compared with groups 2 and 3 (all p values <.01). In addition, connexin43 and endothelial nitric oxide synthase messenger RNA gene expressions of lung and right ventricle and Bcl-2 protein expression of right ventricle were significantly lower in group 1 than in groups 2 and 3 (all p values <.01). Furthermore, the number of alveolar sacs and small lung arterioles were significantly lower in group 1 than in groups 2 and 3 (all p values <.01).

Conclusions: Autologous bone marrow-derived endothelial progenitor cell transplantation effectively ameliorates MCT-induced pulmonary arterial hypertension.