Published Online
on January 22, 2007

A more recent version of this article appeared on January 30, 2007

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Submitted on August 2, 2006
Accepted on November 13, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: msata-circ{at}umin.ac.jp.

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.

Key words: bone marrow • hypertension, pulmonary • monocrotaline • myocytes, smooth muscle

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