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1Cardiovascular Research Center, Department of Medicine, and 2Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129; 3Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; 4Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan
Submitted 25 June 2004 ; accepted in final form 24 July 2004
Heterozygous mutations of the bone morphogenetic protein type II receptor (BMPR-II) gene have been identified in patients with primary pulmonary hypertension. The mechanisms by which these mutations contribute to the pathogenesis of primary pulmonary hypertension are not fully elucidated. To assess the impact of a heterozygous mutation of the BMPR-II gene on the pulmonary vasculature, we studied mice carrying a mutant BMPR-II allele lacking exons 4 and 5 (BMPR-II+/– mice). BMPR-II+/– mice had increased mean pulmonary arterial pressure and pulmonary vascular resistance compared with their wild-type littermates. Histological analyses revealed that the wall thickness of muscularized pulmonary arteries (<100 µm in diameter) and the number of alveolar-capillary units were greater in BMPR-II+/– than in wild-type mice. Breathing 11% oxygen for 3 wk increased mean pulmonary arterial pressure, pulmonary vascular resistance, and hemoglobin concentration to similar levels in BMPR-II+/– and wild-type mice, but the degree of muscularization of small pulmonary arteries and formation of alveolar-capillary units were reduced in BMPR-II+/– mice. Our results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing.
pulmonary vasculature; smooth muscle cells; bone morphogenetic protein; hypoxia
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