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
(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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|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
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|
|
|
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|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 R Koehler, E Grunig, M W Pauciulo, M M Hoeper, H Olschewski, H Wilkens, M Halank, J Winkler, R Ewert, H Bremer, et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension J. Med. Genet., December 1, 2004; 41(12): e127 - e127. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
N. Kunichika, J. W. Landsberg, Y. Yu, H. Kunichika, P. A. Thistlethwaite, L. J. Rubin, and J. X.-J. Yuan Bosentan Inhibits Transient Receptor Potential Channel Expression in Pulmonary Vascular Myocytes Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1101 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.B.W.E.M. Roos, G. Pals, P.M. Struycken, G.J.E. Rinkel, M. Limburg, J.C. Pronk, J.S.P. van den Berg, J.A.F.M. Luijten, P.L. Pearson, M. Vermeulen, et al. Genome-Wide Linkage in a Large Dutch Consanguineous Family Maps a Locus for Intracranial Aneurysms to Chromosome 2p13 Stroke, October 1, 2004; 35(10): 2276 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yu, I. Fantozzi, C. V. Remillard, J. W. Landsberg, N. Kunichika, O. Platoshyn, D. D. Tigno, P. A. Thistlethwaite, L. J. Rubin, and J. X.-J. Yuan Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension PNAS, September 21, 2004; 101(38): 13861 - 13866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Takeda, F. Otsuka, K. Nakamura, K. Inagaki, J. Suzuki, D. Miura, H. Fujio, H. Matsubara, H. Date, T. Ohe, et al. Characterization of the Bone Morphogenetic Protein (BMP) System in Human Pulmonary Arterial Smooth Muscle Cells Isolated from a Sporadic Case of Primary Pulmonary Hypertension: Roles of BMP Type IB Receptor (Activin Receptor-Like Kinase-6) in the Mitotic Action Endocrinology, September 1, 2004; 145(9): 4344 - 4354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Humbert, N. W. Morrell, S. L. Archer, K. R. Stenmark, M. R. MacLean, I. M. Lang, B. W. Christman, E. K. Weir, O. Eickelberg, N. F. Voelkel, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 13S - 24S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Newman, R. C. Trembath, J. A. Morse, E. Grunig, J. E. Loyd, S. Adnot, F. Coccolo, C. Ventura, J. A. Phillips III, J. A. Knowles, et al. Genetic basis of pulmonary arterial hypertension: Current understanding and future directions J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 33S - 39S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Weir, Z. Hong, and A. Varghese The Serotonin Transporter: A Vehicle to Elucidate Pulmonary Hypertension? Circ. Res., May 14, 2004; 94(9): 1152 - 1154. [Full Text] [PDF]
|
|
|
|
|
|
E. Marcos, E. Fadel, O. Sanchez, M. Humbert, P. Dartevelle, G. Simonneau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension Circ. Res., May 14, 2004; 94(9): 1263 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. West, K. Fagan, W. Steudel, B. Fouty, K. Lane, J. Harral, M. Hoedt-Miller, Y. Tada, J. Ozimek, R. Tuder, et al. Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle Circ. Res., April 30, 2004; 94(8): 1109 - 1114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Budhiraja, R. M. Tuder, and P. M. Hassoun Endothelial Dysfunction in Pulmonary Hypertension Circulation, January 20, 2004; 109(2): 159 - 165. [Full Text] [PDF]
|
|
|
|
|
|
C. V. Remillard and J. X.-J. Yuan Activation of K+ channels: an essential pathway in programmed cell death Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L49 - L67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. Blanpain, E. Le Poul, J. Parma, C. Knoop, M. Detheux, M. Parmentier, G. Vassart, and M. J Abramowicz Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension Cardiovasc Res, December 1, 2003; 60(3): 518 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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. |