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Pulmonary Hypertension Due to BMPR2 Mutation

A New Paradigm for Tissue Remodeling?

Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Nicholas W. Morrell, M.A., M.D., F.R.C.P., Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk

ABSTRACT

Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-ß. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-ß signaling and altered cellular responses to TGF-ß. The likely mechanism involves an interaction between BMP and TGF-ß–regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-ß and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.

Key Words: genetics • pulmonary arterial hypertension • transforming growth factor-ß

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