on March 25, 2002
Circulation. 2002
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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Submitted on November 16, 2001
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. * To whom correspondence should be addressed. 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.
Revised on January 23, 2002
Accepted on January 29, 2002
Primary Pulmonary Hypertension Is
Associated With Reduced Pulmonary Vascular Expression of Type
II Bone Morphogenetic Protein Receptor
Carl Atkinson BSc,
Key words: hypertension, pulmonary • immunohistochemistry • receptors
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R. D. Machado, N. Rudarakanchana, C. Atkinson, J. A. Flanagan, R. Harrison, N. W. Morrell, and R. C. Trembath Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension Hum. Mol. Genet., December 15, 2003; 12(24): 3277 - 3286. [Abstract] [Full Text] [PDF]
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C. J. Favre, M. Mancuso, K. Maas, J. W. McLean, P. Baluk, and D. M. McDonald Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1917 - H1938. [Abstract] [Full Text] [PDF]
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S. Zhang, I. Fantozzi, D. D. Tigno, E. S. Yi, O. Platoshyn, P. A. Thistlethwaite, J. M. Kriett, G. Yung, L. J. Rubin, and J. X.-J. Yuan Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L740 - L754. [Abstract] [Full Text] [PDF]
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P. N. Kao and J. L. Faul Emerging therapies for pulmonary hypertension: Striving for efficacy and safety J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2126 - 2129. [Full Text] [PDF]
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M. Rindermann, E. Grunig, A. von Hippel, R. Koehler, G. Miltenberger-Miltenyi, D. Mereles, K. Arnold, M. Pauciulo, W. Nichols, H. Olschewski, et al. Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31 J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2237 - 2244. [Abstract] [Full Text] [PDF]
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E. C. Delot, M. E. Bahamonde, M. Zhao, and K. M. Lyons BMP signaling is required for septation of the outflow tract of the mammalian heart Development, January 1, 2003; 130(1): 209 - 220. [Abstract] [Full Text] [PDF]
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S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot Pathobiology of pulmonary arterial hypertension Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572. [Abstract] [Full Text] [PDF]
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T. Nishimura, J. L. Faul, G. J. Berry, L. T. Vaszar, D. Qiu, R. G. Pearl, and P. N. Kao Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., November 15, 2002; 166(10): 1403 - 1408. [Abstract] [Full Text] [PDF]
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N. Rudarakanchana, J. A. Flanagan, H. Chen, P. D. Upton, R. Machado, D. Patel, R. C. Trembath, and N. W. Morrell Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension Hum. Mol. Genet., June 15, 2002; 11(13): 1517 - 1525. [Abstract] [Full Text] [PDF]
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