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(Circulation. 2007;115:509-517.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Diverse Contribution of Bone Marrow–Derived Cells to Vascular Remodeling Associated With Pulmonary Arterial Hypertension and Arterial Neointimal Formation

Makoto Sahara, MD; Masataka Sata, MD; Toshihiro Morita, MD; Kazuto Nakamura, MD; Yasunobu Hirata, MD; Ryozo Nagai, MD

From the Department of Cardiovascular Medicine (M. Sahara, M. Sata, T.M., K.N., Y.H., R.N.) and Department of Advanced Clinical Science and Therapeutics (M. Sata), University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Correspondence to Masataka Sata, MD, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.ac.jp

Received August 2, 2006; accepted November 13, 2006.

Background— Recent evidence suggests that bone marrow (BM)–derived cells may differentiate into vascular cells that participate in arterial repair and/or lesion formation. However, it remains uncertain whether BM-derived cells also can participate in vascular remodeling associated with pulmonary arterial hypertension.

Methods and Results— The BM of Sprague-Dawley rats was reconstituted with that of green fluorescent protein–transgenic rats. The BM-chimeric rats were injected intraperitoneally with 60 mg/kg monocrotaline after unilateral subpneumonectomy, and they concurrently underwent wire-mediated endovascular injury in femoral artery. After 28 days, they had elevated right ventricular systolic pressure (58.8±5.4 versus 20.4±2.4 mm Hg in sham-control; P<0.01). The pulmonary arterioles were markedly thickened, with an infiltration of green fluorescent protein–positive macrophages into the perivascular areas. The endothelium of pulmonary arterioles contained only a few green fluorescent protein–positive cells, and green fluorescent protein–positive cells were seldom detected as smooth muscle cells in the lesions of thickened pulmonary arterioles. In contrast, BM-derived smooth muscle–like cells could be readily detected in the thickened neointima and media of the wire-injured femoral artery. Moreover, intravenous injection of 1x10⁸ BM cells from young rats had no beneficial effects on pulmonary hypertension, pulmonary arterial remodeling, or survival in the aged rats treated with monocrotaline plus unilateral subpneumonectomy. No injected BM cell was identified as an endothelial cell or a smooth muscle cell.

Conclusions— These results suggest that BM-derived cells can participate in arterial neointimal formation after mechanical injury, whereas they do not contribute substantially to pulmonary arterial remodeling associated with monocrotaline-induced pulmonary arterial hypertension in the pneumonectomized rats.

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