Abstract 759: Diverse Contribution of Bone Marrow-Derived Cells to Vascular Remodeling between Systemic Arteries Injured Mechanically and Pulmonary Vasculature Injured by Monocrotaline Combined with Subpneumonectomy
Background: Recent evidence suggests that bone marrow (BM)-derived cells may differentiate into vascular cells participating in vascular remodeling. Here, we rigorously tested and compared the contribution of BM-derived cells to vascular remodeling between systemic arteries injured mechanically and pulmonary vasculature injured by monocrotaline (MCT) combined with unilateral subpneumonectomy (USP) inducing severe pulmonary hypertension.
Methods and Results: Wild Sprague-Dawley rats were lethally irradiated and injected intravenously with sufficient BM cells derived from green fluorescent protein (GFP)-transgenic rats. Four weeks after highly successful BM transplantation (replacement rate ≥ 85%), the chimeric rats (n=20) underwent balloon- or wire-mediated endovascular injuries in carotid arteries (CAs) or femoral arteries (FAs), and they were concurrently injected intraperitoneally with 60 mg/kg MCT combined with or without USP. At 4 weeks, the injured CAs or FAs showed marked neointimal hyperplasia composed of α-smooth muscle actin-positive (αSMA+) cells. Some of αSMA+ cells in the thickened neointima and media were also positive for GFP. Then, they concurrently had elevated right ventricular systolic pressure (58.7±5.7 mmHg in MCT+USP-group and 49.7±4.3 mmHg in MCT-group; p<0.0001 vs. 20.8±3.8 mmHg in sham-control, respectively) with marked medial thickening of pulmonary arterioles (PAs) composed of αSMA+ cells. However, GFP+ cells were seldom detected among αSMA+ cells in the thickened PAs (p<0.0001 vs. CAs or FAs), and also seldom detected among CD31+ cells of PAs. Histologically, small PAs of MCT-lungs were frequently occluded by thromboemboli along with the damage and/or apoptosis of vascular endothelial cells. The broad occlusion of pulmonary microvasculature induces an elevation of pulmonary vascular resistance, resulting in the thickening of PAs. This pathological process in PAs may be associated with the diverse contribution of BM-derived cells to each vascular remodeling.
Conclusions: These results suggest that BM-derived cells can contribute to systemic arterial remodeling, whereas they do not contribute substantially to pulmonary arterial remodeling in MCT-induced pulmonary hypertension of rats.