Circulation. 2002;105:1672-1678
Published online before print March 25, 2002, doi: 10.1161/01.CIR.0000012754.72951.3D
Published online before print March 25, 2002, doi: 10.1161/01.CIR.0000012754.72951.3D
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(Circulation. 2002;105:1672.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor
From the Department of Medicine (N.W.M., P.D.U.), University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK; Department of Pathology (C.A., S.S.), Papworth Hospital, Cambridge, UK; and Division of Medical Genetics (R.M., J.R.T., R.C.T.), University of Leicester, Leicester, UK.
Correspondence to Dr Nicholas W. Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Box 157, Hills Rd, Cambridge CB2 2QQ, UK. E-mail nwm23{at}cam.ac.uk
Background— Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-ß (TGF-ß) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).
Methods and Results— Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-ß by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-ßRII or the endothelial marker CD31.
Conclusions— The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.
Key Words: hypertension, pulmonary • immunohistochemistry • receptors
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