doi: 10.1161/hc3201.094152
(Circulation. 2001;104:790.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-ß1 and Bone Morphogenetic Proteins
From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom.
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
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
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 cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-ß superfamily members.
Methods and Results— For studies of 3H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-ß1 (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated 3H-thymidine incorporation, and TGF-ß1 and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-ß1 stimulated 3H-thymidine incorporation (200%; P<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription–polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-ßRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-ßRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with 125I-TGF-ß1 confirmed that the abnormal responses in PPH cells were not due to differences in TGF-ß receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-ßRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates.
Conclusions— We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-ß1 and BMPs and that altered integration of TGF-ß superfamily growth signals may contribute to the pathogenesis of PPH.
Key Words: hypertension, pulmonary • muscle, smooth • growth substances • proteins
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Primary pulmonary hypertension (PPH) is a rare disorder that is progressive and often fatal.1 The disease is characterized by vascular cell proliferation and obliteration of small pulmonary arteries,2 leading to severe pulmonary hypertension and right ventricular failure. Typical morphological changes include increased muscularization of small arteries and thickening or fibrosis of the intima, as well as the presence of plexiform lesions, which are tangles of capillary-like channels adjacent to small pulmonary arteries.3
Recently, linkage was established between familial PPH and a region on the long arm of chromosome 2 (2q33).4,5 Sequencing of positional candidate genes revealed heterozygous mutations involving the gene encoding the type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor-ß (TGF-ß) superfamily of receptors.6,7 The heterogeneous mutations include frameshift and nonsense mutations predicted to cause premature truncation of the 1038 amino acid protein. Missense mutations occur at highly conserved and functionally important sites, predicted to perturb ligand binding or disrupt the kinase domain of the receptor. Interestingly, the same mutations underlie 
25% of apparently sporadic cases of PPH, some of which are in fact familial, the remainder arising de novo.8 Although these recent genetic studies point toward a critical role for the TGF-ß superfamily in the regulation of pulmonary vascular cell growth and differentiation, the precise molecular mechanisms leading to disease pathogenesis remain to be elucidated.
The recognized role of the TGF-ß superfamily in endothelial9 and smooth muscle10 cell growth, differentiation, and matrix production reinforces the potential role of BMPR-II in the vascular lesion of PPH. Growth, migration, and excess matrix deposition by endothelial cells, smooth muscle cells, and adventitial fibroblasts all contribute to the process of vascular wall remodeling in pulmonary hypertension.11 TGF-ß1 exerts potent effects on vascular smooth muscle cells in vitro, including inhibition of proliferation,12 extracellular matrix synthesis, and cell differentiation.13 Bone morphogenetic proteins (BMPs) have been less extensively studied, but BMP-7 has been shown to inhibit proliferation of human aortic smooth muscle cells and increase expression of smooth muscle differentiation markers,14 and BMP-2 inhibits vascular smooth muscle cell proliferation after balloon injury in rats.15
Taken together, these studies provide a platform from which to speculate that disruption of TGF-ß superfamily signaling as a consequence of BMPR2 mutation in PPH might contribute to the cellular proliferation and vascular obliteration seen in this condition. The present study demonstrates that cells from patients with PPH but not control subjects or patients with secondary pulmonary hypertension (SPH) exhibit abnormal growth responses to TGF-ß1 and BMPs, which suggests that altered integration of TGF-ß superfamily signals may contribute to the vascular lesions characteristic of PPH.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Isolation of Human Pulmonary Artery Smooth Muscle Cells
Proximal segments of human pulmonary artery were obtained from patients undergoing lung or heart-lung transplantation for PPH (n=6) or pulmonary hypertension secondary to congenital heart disease (n=5). Samples of proximal pulmonary artery were obtained from unused donors for transplantation (n=9). The study was approved by the Harefield and Papworth Hospital ethical review committees, and subjects gave informed written consent. Explants were processed as described previously.16 Cells were used for experiments between passages 4 and 8, and the smooth muscle phenotype of isolated cells was confirmed by positive immunofluorescence with antibodies to anti-smooth muscle-
actin antibody (IA4) and anti-smooth muscle–specific myosin (hsm-v), as described.16
Growth Studies
To determine the serum-stimulated growth rates, cells were seeded at 104 per well in 48-well plates in DMEM/10% FBS. Cell numbers were counted with a hemocytometer at days 2, 5, and 7. In additional studies, BMP-2, -4, or -7 (1 to 100 ng/mL) or TGF-ß1 (0.1 to 10 ng/mL) was added to quiescent cells (0.1% FBS) or serum-stimulated cells (10% FBS) to determine the effect on proliferation. Growth of human pulmonary artery smooth muscle cells (PASMCs) in response to individual growth factors was determined by [methyl-3H]-thymidine incorporation, representing DNA synthesis.16 Cells were grown to 70% to 80% confluence and made quiescent by incubation with DMEM/0.1% FBS for 48 hours. The media was then exchanged for fresh DMEM/0.1% FBS either alone or containing BMP-2, -4, or -7 (0.1 to 100 ng/mL), TGF-ß1 (0.1 to 100 ng/mL), platelet-derived growth factor-BB (PDGF-BB; 10 ng/mL), or thrombin (3 U/mL) for 24 hours. Then, 0.5 µCi/well [methyl-3H]-thymidine was added for the final 6 hours. Each isolate was studied at least twice under each condition, and the mean values were taken from all studies conducted with any one isolate.
Expression Profiling of TGF-ß Superfamily Receptors by Reverse Transcription–Polymerase Chain Reaction
Total RNA was isolated from growth-arrested primary cultures of human PASMCs with TRIzol reagent (Life Technologies) and reverse transcription–polymerase chain reaction (RT-PCR) performed with the Access RT-PCR System from Promega. Primers were taken from previously published sequences, where possible, or designed with the computer program Prime(+). The primer sequences and sources are available online in Table I. All primers were synthesized by Sigma-Genosys Ltd. PCR products were visualized by electrophoresis in agarose (2%) gels stained with ethidium bromide. Control reactions were run without the addition of reverse transcriptase. The identity of PCR products was confirmed by direct sequencing.
Receptor Binding Studies in Cells
For competition binding studies, cells were seeded in 24-well plates and grown to confluence, then made quiescent by incubation in 0.1% FBS for 3 days. 125I-TGF-ß1 competition binding was performed as described previously.17 Cells were incubated at 4°C for 4 hours with DMEM/0.5% BSA containing 125I-TGF-ß1 (Amersham) in the absence or presence of unlabeled TGF-ß1 (0.01 to 100 ng/mL). The effect of BMP-2, BMP-4, or BMP-7 (10 to 100 ng/mL) on binding was also assessed.
Receptor Cross-Linking Studies
For cross-linking studies, cells were seeded in 6-well plates and grown to confluence. Cells were then made quiescent as described above. The initial binding steps were as described above except that the ligand was added at 10 000 to 20 000 cps/well in the absence or presence of 100 ng/mL TGF-ß1 or BMP-4. Cross-linking of 125I-TGF-ß1 to cell surface receptors was performed by a previously described technique, with minor modifications.18 Samples were separated with 10% PAGE gels with or without 50 mmol/L DTT, stained with Coomassie blue, dried, and exposed to autoradiographic film.
Screening for Mutations in the ALK1, BMPR-II, and TGF-ßRII Genes
Genomic DNA was extracted from smooth muscle cells by standard techniques (Nucleon Biosciences). Protein coding sequence from the ALK1 gene (exons 2 to 10) was amplified from genomic DNA with primers complimentary to the intron sequences, as described previously,19 and sequenced with a dye-terminator cycle-sequencing system (ABI PRISM 377, Perkin-Elmer Applied Biosystems). BMPR-II sequence (exons 1 to 13) analysis was performed, as described previously and with primer sequences available on the Internet.20 In addition, we looked for mutations in the A10 microsatellite region of TGF-ßRII, as described previously.12 This region is prone to 1- or 2-bp deletions that lead to premature truncation of the protein and a reduction in gene expression and has been associated with a loss of responsiveness to the growth inhibitory effects of TGF-ß1 in vascular smooth muscle cells12 and tumor cells.21
Statistical Analysis
Data were expressed as mean±SEM and analyzed with GraphPad Prism version 3.0 (GraphPad Software). Comparisons were made by Student’s t test or1-way ANOVA with the Tukey post hoc test as appropriate. A value of P<0.05 indicated statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical Characteristics of Pulmonary Hypertensive Patients
The clinical and demographic information available for pulmonary hypertensive cases is shown in the Table.
|
Effect of TGF-ß1 and BMPs on DNA Synthesis
In control cells, PDGF (10 ng/mL) and thrombin (3 U/mL) led to an increase in 3H-thymidine incorporation of 284±62% and 149±14%, respectively. The response was similar in cells from patients with PPH (PDGF 277±31%; thrombin 189±10%) and SPH (PDGF 367±61%, thrombin 174±12%; P>0.05). In contrast, clear differences were demonstrated in the response of PASMCs from PPH patients (compared with SPH and normal controls) to TGF-ß1 and BMPs. Incubation of serum-deprived donor or SPH PASMCs with TGF-ß1 led to inhibition of basal 3H-thymidine incorporation at 24 hours (Figure 1). In PPH cells, TGF-ß1 consistently stimulated 3H-thymidine incorporation (Figure 1). In serum-stimulated PASMCs, a similar inhibition of 3H-thymidine incorporation by TGF-ß1 was observed in PASMCs from controls and patients with SPH, whereas stimulation was still apparent in PPH cells (data not shown).
|
Incubation of serum-deprived control and SPH PASMCs with BMP-2, -4, or -7 led to inhibition of basal and serum-stimulated 3H-thymidine incorporation at 24 hours (Figure 2). However, BMPs failed to significantly suppress basal and serum-stimulated 3H-thymidine incorporation in cells from patients with PPH (Figure 2).
|
Effect of TGF-ß1 and BMPs on Proliferation
Analysis of growth curves of cells from controls and patients with PPH and SPH revealed no difference in the rate of serum-stimulated proliferation over a 15-day period (Figure 3), which suggests that PASMCs from patients with PPH do not possess an intrinsically enhanced growth response to nonspecific mitogenic stimuli. The effect of TGF-ß1 and BMPs on serum-stimulated proliferation of PASMCs was also examined. TGF-ß1 and BMP-2, -4, and -7 all inhibited the serum-stimulated proliferation of PASMCs from normal subjects and patients with SPH (Figure 4). In contrast, TGF-ß1 enhanced the serum-stimulated proliferation of PASMCs from PPH patients. Furthermore, BMPs failed to significantly reduce proliferation rates of PASMCs from patients with PPH (Figure 4).
|
|
Expression Profile of TGF-ß Superfamily Receptors
mRNA transcripts for TGF-ß superfamily type I (ALK-1, TGF-ßRI, Act RI, and BMP RIB) and type II (TGF-ßRII, BMPR-II, ActR2, and ActR2B) receptors were present in total RNA isolated from PASMCs (Figure 5). We were unable to detect mRNA transcripts for BMP RIA. Specificity of the reactions for RNA was confirmed by the absence of PCR products when samples were run without reverse transcriptase.
|
Receptor Binding Studies
Specific binding of 125I-TGF-ß1 was demonstrated in cells from controls and PPH patients and was 50% of total binding. Competition binding curves demonstrated concentration-dependent competition by unlabeled ligand (Figure 6). 125I-TGF-ß1 binding was not inhibited by an excess of unlabeled BMP-2, -4, or -7 (100 ng/mL; data not shown). The affinity (IC50) of this site was similar in PASMCs from patients with PPH (1.23±0.39 ng/mL; n=3), patients with SPH (2.18±0.26 ng/mL; n=3), and controls (1.07±0.35 ng/mL; n=4). In addition, binding site density was similar in PPH (10 329±1659 sites/cell), SPH (10 350±750 sites/cell), and controls (10 966±2918 sites/cell).
|
Receptor Cross-Linking
One potential mechanism for the divergent functional responses to TGF-ß1 in PPH smooth muscle cells is an alteration in the proportion of type I and type II receptors.18 Analysis of cross-linking gels indicated that the proportion of total binding of 125I-TGF-ß1 to bands corresponding to TGF-ßRI, TGF-ßRII, and TGF-ßRIII was similar in cells derived from patients and controls (Figure 7). In addition, BMP-4 failed to compete for 125I-TGF-ß1 binding.
|
Mutation Analysis
We found no evidence of mutation in the coding sequence of ALK-1 or the A10 microsatellite region of TGF-ßRII. Mutation analysis of the coding region of BMPR2 in 5 samples from patients with PPH revealed a missense (C to T at position 1471) mutation in exon 11 in 1 patient with apparently sporadic PPH. The mutation is predicted to lead to substitution of a tryptophan for the arginine residue at position 491 of the amino acid sequence, within the kinase domain of the BMPR-II receptor. An additional PASMC isolate was derived from a patient with familial PPH in whom linkage had previously been established with 2q33, the chromosomal region containing BMPR2, although no specific mutations were identified.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The main finding of this study is that smooth muscle cells isolated from the pulmonary artery of patients with PPH exhibit altered growth responses to the BMPR-II ligands BMP-2, -4, and -7 compared with cells isolated from normal controls or patients with a similar degree of pulmonary hypertension secondary to congenital heart disease. Another finding was that PASMCs from patients with PPH exhibit a heightened growth response to TGF-ß1, which is not a known ligand for BMPR-II, suggesting more widespread disruption of TGF-ß superfamily signaling in these cells. Moreover, our data suggest that the mechanism for the altered growth response to TGF-ß1 is not due to alterations in TGF-ß type I/type II receptor ratios or downregulation of the TGF-ßRII receptor.
These studies were prompted by the recent discovery that mutations in BMPR2 underlie many cases of familial and sporadic PPH.6,8 Because hypertrophy and hyperplasia of vascular smooth muscle and endothelial cells almost certainly contribute to the formation of obliterative lesions in PPH, we hypothesized that deleterious BMPR2 mutations might disrupt the growth-inhibitory effects of TGF-ß superfamily members on vascular smooth muscle. Although the effects of BMPR-II mutation on endothelial function remain to be determined, our findings support this hypothesis and point toward a common molecular defect in PASMCs from patients with PPH. Despite this, we identified a BMPR2 mutation in only 1 of 5 patients with apparently sporadic PPH. This is consistent with the reported frequency of BMPR-II mutations of 26% in patients with "sporadic" PPH.8 However, it is likely that the actual frequency of BMPR2 mutations in PPH is higher than this, because the direct sequencing methods used in this and other studies may not detect mutations in regulatory regions or large gene deletions or rearrangements. The remaining PPH case in the present study had familial PPH and came from a family in which linkage was established with the BMPR2 locus, although again, no mutation was identified. We have recently found that mutations in Alk-1, which encodes an orphan TGF-ß type I receptor, may also be associated with PPH in families with the condition hereditary hemorrhagic telangiectasia (R.C.T., unpublished observations, 2001). However, screening of ALK-1 revealed no mutations in the present study.
Our RT-PCR data are consistent with a previous report showing expression of multiple type I receptors for the TGF-ß superfamily in rat aortic smooth muscle.22 Although the expression of TGF-ßRII by vascular smooth muscle is well documented,10,18 there is little information regarding the expression of BMPR-II by vascular cells. Binding sites for 125I-BMP2 have been identified on a wide variety of cell lines derived from fibroblasts, keratinocytes, astrocytes and kidney epithelial cells, as well as tumor cells from diverse organs,23 although BMP2 can also bind to the type II receptor Act RIIB.
Numerous studies have examined the effects of TGF-ß1 on vascular smooth muscle biology. The effects of TGF-ß1 on cell growth are context specific in that they depend on the developmental stage at which cells are studied, the tissue of origin, and the presence of other regulatory factors.24 In general, TGF-ß1 inhibits the proliferation and migration of smooth muscle and endothelial cells,25 most likely by inhibition of cyclin-dependent kinases and by downregulation of c-myc.24 The effects of BMPs on vascular cell growth have been less extensively investigated, but the emerging consensus is that BMPs inhibit the proliferation of vascular smooth muscle15 and promote differentiation of smooth muscle phenotype,14 although stimulation of vascular smooth muscle cell chemotaxis has also been reported.26 Although the present study showed clear differences in the response to TGF-ß1 and BMPs in PPH cells, one potential limitation is that we used cells from large proximal vessels rather than peripheral arteries, which are considered the main site of disease.
Although these studies demonstrate one of the important functional consequences of dysfunctional BMPR-II signaling in PASMCs, the precise molecular mechanism of the altered responses to BMPs remains to be determined in PPH. Transient transfection of cell lines with mutant BMPR-II led to reduced activation of a luciferase reporter construct containing a Smad binding element, which suggests impaired signaling by Smad proteins.27 The surprising finding in the present study was the stimulation of DNA synthesis and proliferation in response to TGF-ß1 in PPH cells. Our data and those of others suggests that TGF-ß1 is not a ligand for the BMPR-II receptor,23 which indicates that dysfunctional TGF-ß superfamily signaling in PPH cells is more widespread than suggested by mutations in BMPR-II alone. Potential mechanisms for the abnormal response to TGF-ß1 include loss of TGF-ßRII receptor function, which commonly occurs as a somatic mutation in pancreatic and colonic tumors.25,28 However, our mutation analysis, receptor binding, and cross-linking data suggest that an alternative mechanism exists for altered TGF-ß1 responses in PPH cells. An alternative mechanism may involve reduced activation of inhibitory Smad proteins as a consequence of loss of BMPR-II function, which alters the response to other TGF-ß superfamily members. In support of this, BMPs are potent inducers of the inhibitory Smads 6 and 7,29 which feed back to inhibit TGF-ß receptor signaling. Loss of Smad 6 and Smad 7 negative feedback might have a permissive effect on TGF-ß1–induced proliferative responses. In epithelial cells, resistance to the antiproliferative action of TGF-ß is a consequence of failure to downregulate c-Myc and to prevent cyclin-dependent kinase inhibitory gene responses.24 The role of these pathways in the abnormal TGF-ß1–induced proliferation of PPH cells requires further study. Furthermore, our results do not explain the selectivity of PPH for the pulmonary as opposed to the systemic circulation. Because systemic vascular cells will be similarly affected by germline mutations in BMPR2, additional factors must determine pulmonary vascular selectivity.
In summary, the present study demonstrates that an important functional abnormality of PASMCs isolated from patients with PPH is resistance to the antiproliferative effects of TGF-ß1 and BMPs. This abnormality may result directly from mutations/dysfunction in BMPR-II and/or closely related signaling pathways. The TGF-ß superfamily plays a critical role in the development and maintenance of the integrity of the normal vasculature. Thus, the altered cellular responses may contribute to the formation of lesions that lead to the vascular obliteration observed in the pulmonary arteries of patients with PPH.
|
Acknowledgments |
|---|
This study was supported by the British Heart Foundation (program grant RG/2000012 to Drs Trembath and Morrell). Dr Morrell was funded by a Medical Research Council Clinician Scientist Fellowship.
|
Footnotes |
|---|
Table I can be found Online at http://www.circulationaha.org
Received March 15, 2001; revision received June 1, 2001; accepted June 4, 2001.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336: 111–117.
2.
Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. Circulation. 1989; 80: 1198–1206.
3.
Cool CD, Stewart JS, Werahera P, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Am J Pathol. 1999; 155: 411–419.
4.
Deng Z, Haghighi F, Helleby L, et al. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med. 2000; 161: 1055–1059.
5. Nichols WC, Koller DL, Slovis B, et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet. 1997; 15: 277–280.[Medline] [Order article via Infotrieve]
6. The International PPH Consortium, Lane KB, Machado RD, et al. Heterozygous germ-line mutations in BMPR2, encoding a TGF-ß receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000; 26: 81–84.[Medline] [Order article via Infotrieve]
7. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000; 67: 737–744.[Medline] [Order article via Infotrieve]
8.
Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-ß family. J Med Genet. 2000; 37: 741–745.
9. Pepper MS. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 1997; 8: 21–43.[Medline] [Order article via Infotrieve]
10. McCaffrey TA. TGF-ßs, and TGF-ß receptors in atherosclerosis. Cytokine Growth Factor Rev. 2000; 11: 103–114.[Medline] [Order article via Infotrieve]
11. Stenmark KR, Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol. 1997; 59: 89–144.[Medline] [Order article via Infotrieve]
12. McCaffrey TA, Du B, Consigli S, et al. Genomic instability in the type II TGF-ß1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin Invest. 1997; 100: 2182–2188.[Medline] [Order article via Infotrieve]
13.
Adam PJ, Regan CP, Hautmann MB, et al. Positive- and negative-acting Kruppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo. J Biol Chem. 2000; 275: 37798–37806.
14. Dorai H, Vukicevic S, Sampath TK. Bone morphogenetic protein-7 (OP-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J Cell Physiol. 2000; 184: 37–45.[Medline] [Order article via Infotrieve]
15. Nakaoka T, Gonda K, Ogita T, et al. Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2. J Clin Invest. 1997; 100: 2824–2832.[Medline] [Order article via Infotrieve]
16.
Morrell NW, Upton PD, Kotecha S, et al. Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors. Am J Physiol. 1999; 277: L440–L448.
17. Gao C, Gressner G, Zoremba M, et al. Transforming growth factor ß (TGF-ß) expression in isolated and cultured rat hepatocytes. J Cell Physiol. 1996; 167: 394–405.[Medline] [Order article via Infotrieve]
18. McCaffrey TA, Consigli S, Du B, et al. Decreased type I/type II TGF-ß receptor ratio in cells derived from human atherosclerotic lesions. J Clin Invest. 1995; 96: 2667–2675.
19. Berg JN, Gallione CJ, Stenzel TT, et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997; 61: 60–67.[Medline] [Order article via Infotrieve]
20. BMPR2 Primer sequences. Available at: http://www. leicester.ac.uk/ge/rt7/index.html. Accessed 2001.
21. Kim S-J, Im Y-H, Markowitz SD, et al. Molecular mechanisms of inactivation of TGF-b receptors during carcinogenesis. Cytokine Growth Factor Rev. 2000; 11: 159–168.[Medline] [Order article via Infotrieve]
22. Agrotis A, Samuel M, Prapas G, et al. Vascular smooth muscle cells express multiple type I receptors for TGF-b, activin, and bone morphogenetic proteins. Biochem Biophys Res Commun. 1996; 219: 613–618.[Medline] [Order article via Infotrieve]
23.
Iwasaki S, Tsuruoka N, Hattori A, et al. Distribution and characterization of specific cellular binding proteins for bone morphogenetic protein-2. J Biol Chem. 1995; 270: 5476–5482.
24. Massagué J, Blain SW, Lo RS. TGFß signaling in growth control, cancer, and heritable disorders. Cell. 2000; 103: 295–309.[Medline] [Order article via Infotrieve]
25.
Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor ß in human disease. N Engl J Med. 2000; 342: 1350–1358.
26. Willette RN, Gu JL, Lysko PG, et al. BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res. 1999; 36: 120–125.[Medline] [Order article via Infotrieve]
27. Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001; 68: 92–102.[Medline] [Order article via Infotrieve]
28.
Grady WM, Rajput A, Myeroff L, et al. Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res. 1998; 58: 3101–3104.
29. Afrakhte M, Moren A, Jossan S, et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-ß family members. Biochem Biophys Res Commun. 2000; 249: 505–511.
This article has been cited by other articles:
 |
|
 |
|
  L. Dewachter, S. Adnot, C. Guignabert, L. Tu, E. Marcos, E. Fadel, M. Humbert, P. Dartevelle, G. Simonneau, R. Naeije, et al. Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension Eur. Respir. J., November 1, 2009; 34(5): 1100 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Selimovic, C-H. Bergh, B. Andersson, E. Sakiniene, H. Carlsten, and B. Rundqvist Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension Eur. Respir. J., September 1, 2009; 34(3): 662 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Huang, D. Wang, K. Ihida-Stansbury, P. L. Jones, and J. F. Martin Defective pulmonary vascular remodeling in Smad8 mutant mice Hum. Mol. Genet., August 1, 2009; 18(15): 2791 - 2801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Ghofrani, R. J. Barst, R. L. Benza, H. C. Champion, K. A. Fagan, F. Grimminger, M. Humbert, G. Simonneau, D. J. Stewart, C. Ventura, et al. Future perspectives for the treatment of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S108 - S117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Upton, R. J. Davies, R. C. Trembath, and N. W. Morrell Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells J. Biol. Chem., June 5, 2009; 284(23): 15794 - 15804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Shintani, H Yagi, T Nakayama, T Saji, and R Matsuoka A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension J. Med. Genet., May 1, 2009; 46(5): 331 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ismail, A. Sturrock, P. Wu, B. Cahill, K. Norman, T. Huecksteadt, K. Sanders, T. Kennedy, and J. Hoidal NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3 Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L489 - L499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Long, A. Crosby, X. Yang, M. Southwood, P. D. Upton, D.-K. Kim, and N. W. Morrell Altered Bone Morphogenetic Protein and Transforming Growth Factor-{beta} Signaling in Rat Models of Pulmonary Hypertension: Potential for Activin Receptor-Like Kinase-5 Inhibition in Prevention and Progression of Disease Circulation, February 3, 2009; 119(4): 566 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Thomas, C. Docx, A. M. Holmes, S. Beach, N. Duggan, K. England, C. Leblanc, C. Lebret, F. Schindler, F. Raza, et al. Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by Monocrotaline Am. J. Pathol., February 1, 2009; 174(2): 380 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Steiner, O. L. Syrkina, N. Kolliputi, E. J. Mark, C. A. Hales, and A. B. Waxman Interleukin-6 Overexpression Induces Pulmonary Hypertension Circ. Res., January 30, 2009; 104(2): 236 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Davies and N. W. Morrell Molecular Mechanisms of Pulmonary Arterial Hypertension: Role of Mutations in the Bone Morphogenetic Protein Type II Receptor Chest, December 1, 2008; 134(6): 1271 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Bull, C. A. Meadows, C. D. Coldren, M. Moore, S. M. Sotto-Santiago, S. P. Nana-Sinkam, T. B. Campbell, and M. W. Geraci Human Herpesvirus-8 Infection of Primary Pulmonary Microvascular Endothelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 2008; 39(6): 706 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Marsboom and S. L. Archer Pathways of Proliferation: New Targets to Inhibit the Growth of Vascular Smooth Muscle Cells Circ. Res., November 7, 2008; 103(10): 1047 - 1049. [Full Text] [PDF]
|
|
|
|
|
|
E. D. Michelakis, M. R. Wilkins, and M. Rabinovitch Emerging Concepts and Translational Priorities in Pulmonary Arterial Hypertension Circulation, September 30, 2008; 118(14): 1486 - 1495. [Full Text] [PDF]
|
|
|
|
 |
|
 P. R. Rai, C. D. Cool, J. A. C. King, T. Stevens, N. Burns, R. A. Winn, M. Kasper, and N. F. Voelkel The Cancer Paradigm of Severe Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., September 15, 2008; 178(6): 558 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Zaiman, M. Podowski, S. Medicherla, K. Gordy, F. Xu, L. Zhen, L. A. Shimoda, E. Neptune, L. Higgins, A. Murphy, et al. Role of the TGF-{beta}/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 896 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. El-Haroun, D. L. Clarke, K. Deacon, D. Bradbury, A. Clayton, A. Sutcliffe, and A. J. Knox IL-1{beta}, BK, and TGF-{beta}1 attenuate PGI2-mediated cAMP formation in human pulmonary artery smooth muscle cells by multiple mechanisms involving p38 MAP kinase and PKA Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L553 - L562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Asosingh, M. A. Aldred, A. Vasanji, J. Drazba, J. Sharp, C. Farver, S. A.A. Comhair, W. Xu, L. Licina, L. Huang, et al. Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension Am. J. Pathol., March 1, 2008; 172(3): 615 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Yu, D. Y. Deng, H. Beppu, C. C. Hong, C. Lai, S. A. Hoyng, N. Kawai, and K. D. Bloch Bone Morphogenetic Protein (BMP) Type II Receptor Is Required for BMP-mediated Growth Arrest and Differentiation in Pulmonary Artery Smooth Muscle Cells J. Biol. Chem., February 15, 2008; 283(7): 3877 - 3888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Upton, L. Long, R. C. Trembath, and N. W. Morrell Functional Characterization of Bone Morphogenetic Protein Binding Sites and Smad1/5 Activation in Human Vascular Cells Mol. Pharmacol., February 1, 2008; 73(2): 539 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Suzuki, K. Montagne, A. Nishihara, T. Watabe, and K. Miyazono BMPs Promote Proliferation and Migration of Endothelial Cells via Stimulation of VEGF-A/VEGFR2 and Angiopoietin-1/Tie2 Signalling J. Biochem., February 1, 2008; 143(2): 199 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Frank, J. Lowery, L. Anderson, M. Brink, J. Reese, and M. de Caestecker Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L98 - L109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lawrie, E. Waterman, M. Southwood, D. Evans, J. Suntharalingam, S. Francis, D. Crossman, P. Croucher, N. Morrell, and C. Newman Evidence of a Role for Osteoprotegerin in the Pathogenesis of Pulmonary Arterial Hypertension Am. J. Pathol., January 1, 2008; 172(1): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors J. Biol. Chem., December 21, 2007; 282(51): 37244 - 37255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhou, J. Heinke, A. Vargas, S. Winnik, T. Krauss, C. Bode, C. Patterson, and M. Moser ERK signaling is a central regulator for BMP-4 dependent capillary sprouting Cardiovasc Res, December 1, 2007; 76(3): 390 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Sanchez, E. Marcos, F. Perros, E. Fadel, L. Tu, M. Humbert, P. Dartevelle, G. Simonneau, S. Adnot, and S. Eddahibi Role of Endothelium-derived CC Chemokine Ligand 2 in Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1041 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yang, P. J. Lee, L. Long, R. C. Trembath, and N. W. Morrell BMP4 Induces HO-1 via a Smad-Independent, p38MAPK-Dependent Pathway in Pulmonary Artery Myocytes Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 598 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ito, T. Okada, H. Miyashita, T. Nomoto, M. Nonaka-Sarukawa, R. Uchibori, Y. Maeda, M. Urabe, H. Mizukami, A. Kume, et al. Interleukin-10 Expression Mediated by an Adeno-Associated Virus Vector Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats Circ. Res., September 28, 2007; 101(7): 734 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu, J. Wang, B. Kinzel, M. Mueller, X. Mao, R. Valdez, Y. Liu, and E. Li Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity Blood, September 1, 2007; 110(5): 1502 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhao, Z. Liu, Z. Wang, C. Yang, J. Liu, and J. Lu Effect of Prepro-Calcitonin Gene-Related Peptide Expressing Endothelial Progenitor Cells on Pulmonary Hypertension Ann. Thorac. Surg., August 1, 2007; 84(2): 544 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zakrzewicz, M. Hecker, L. M. Marsh, G. Kwapiszewska, B. Nejman, L. Long, W. Seeger, R. T. Schermuly, N. W. Morrell, R. E. Morty, et al. Receptor for Activated C-Kinase 1, a Novel Interaction Partner of Type II Bone Morphogenetic Protein Receptor, Regulates Smooth Muscle Cell Proliferation in Pulmonary Arterial Hypertension Circulation, June 12, 2007; 115(23): 2957 - 2968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zakrzewicz, F. M. Kouri, B. Nejman, G. Kwapiszewska, M. Hecker, R. Sandu, E. Dony, W. Seeger, R. T. Schermuly, O. Eickelberg, et al. The transforming growth factor-{beta}/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension Eur. Respir. J., June 1, 2007; 29(6): 1094 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zhang, H. Dong, L. J. Rubin, and J. X.-J. Yuan Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2297 - C2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Morty, B. Nejman, G. Kwapiszewska, M. Hecker, A. Zakrzewicz, F. M. Kouri, D. M. Peters, R. Dumitrascu, W. Seeger, P. Knaus, et al. Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial Hypertension Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1072 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Reynolds, W. Xia, M. D. Holmes, S. J. Hodge, S. Danilov, D. T. Curiel, N. W. Morrell, and P. N. Reynolds Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1182 - L1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. McMurtry, R. Moudgil, K. Hashimoto, S. Bonnet, E. D. Michelakis, and S. L. Archer Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L872 - L878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. W. Morrell Pulmonary Hypertension Due to BMPR2 Mutation: A New Paradigm for Tissue Remodeling? Proceedings of the ATS, November 1, 2006; 3(8): 680 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lagna, P. H. Nguyen, W. Ni, and A. Hata BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1059 - L1067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Fantozzi, O. Platoshyn, A. H. Wong, S. Zhang, C. V. Remillard, M. R. Furtado, O. V. Petrauskene, and J. X.-J. Yuan Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L993 - L1004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ihida-Stansbury, D. M. McKean, K. B. Lane, J. E. Loyd, L. A. Wheeler, N. W. Morrell, and P. L. Jones Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L694 - L702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bobik Transforming Growth Factor-{beta}s and Vascular Disorders Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1712 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Miriyala, M. C. Gongora Nieto, C. Mingone, D. Smith, S. Dikalov, D. G. Harrison, and H. Jo Bone Morphogenic Protein-4 Induces Hypertension in Mice: Role of Noggin, Vascular NADPH Oxidases, and Impaired Vasorelaxation Circulation, June 20, 2006; 113(24): 2818 - 2825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bonnet, E. D. Michelakis, C. J. Porter, M. A. Andrade-Navarro, B. Thebaud, S. Bonnet, A. Haromy, G. Harry, R. Moudgil, M. S. McMurtry, et al. An Abnormal Mitochondrial-Hypoxia Inducible Factor-1{alpha}-Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats: Similarities to Human Pulmonary Arterial Hypertension Circulation, June 6, 2006; 113(22): 2630 - 2641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Eddahibi, C. Guignabert, A.-M. Barlier-Mur, L. Dewachter, E. Fadel, P. Dartevelle, M. Humbert, G. Simonneau, N. Hanoun, F. Saurini, et al. Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension: Critical Role for Serotonin-Induced Smooth Muscle Hyperplasia Circulation, April 18, 2006; 113(15): 1857 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sturrock, B. Cahill, K. Norman, T. P. Huecksteadt, K. Hill, K. Sanders, S. V. Karwande, J. C. Stringham, D. A. Bull, M. Gleich, et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L661 - L673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takahashi, N. Goto, Y. Kojima, Y. Tsuda, Y. Morio, M. Muramatsu, and Y. Fukuchi Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L450 - L458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Michelakis Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension: Heterogeneous BMP Signaling May Have Therapeutic Implications Circ. Res., February 3, 2006; 98(2): 172 - 175. [Full Text] [PDF]
|
|
|
|
|
|
K. Teichert-Kuliszewska, M. J.B. Kutryk, M. A. Kuliszewski, G. Karoubi, D. W. Courtman, L. Zucco, J. Granton, and D. J. Stewart Bone Morphogenetic Protein Receptor-2 Signaling Promotes Pulmonary Arterial Endothelial Cell Survival: Implications for Loss-of-Function Mutations in the Pathogenesis of Pulmonary Hypertension Circ. Res., February 3, 2006; 98(2): 209 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Caldwell, R. Gadipatti, K. B. Lane, and V. L. Shepherd HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells J. Leukoc. Biol., January 1, 2006; 79(1): 192 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rondelet, F. Kerbaul, R. Van Beneden, I. Hubloue, S. Huez, P. Fesler, M. Remmelink, S. Brimioulle, I. Salmon, and R. Naeije Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2319 - H2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Frank, A. Abtahi, D.J. Yamaguchi, S. Manning, Y. Shyr, A. Pozzi, H. S. Baldwin, J. E. Johnson, and M. P. de Caestecker Bone Morphogenetic Protein 4 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Circ. Res., September 2, 2005; 97(5): 496 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Stewart Bone Morphogenetic Protein Receptor-2 and Pulmonary Arterial Hypertension: Unraveling a Riddle Inside an Enigma? Circ. Res., May 27, 2005; 96(10): 1033 - 1035. [Full Text] [PDF]
|
|
|
|
|
|
X. Yang, L. Long, M. Southwood, N. Rudarakanchana, P. D. Upton, T. K. Jeffery, C. Atkinson, H. Chen, R. C. Trembath, and N. W. Morrell Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension Circ. Res., May 27, 2005; 96(10): 1053 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. D. Zhao, D. W. Courtman, Y. Deng, L. Kugathasan, Q. Zhang, and D. J. Stewart Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow-Derived Endothelial-Like Progenitor Cells: Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease Circ. Res., March 4, 2005; 96(4): 442 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. X.-J. Yuan and L. J. Rubin Pathogenesis of Pulmonary Arterial Hypertension: The Need for Multiple Hits Circulation, February 8, 2005; 111(5): 534 - 538. [Full Text] [PDF]
|
|
|
|
|
|
T. K. Jeffery, P. D. Upton, R. C. Trembath, and N. W. Morrell BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L370 - L378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Beppu, F. Ichinose, N. Kawai, R. C. Jones, P. B. Yu, W. M. Zapol, K. Miyazono, E. Li, and K. D. Bloch BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1241 - L1247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. K. Sheares, T. K. Jeffery, L. Long, X. Yang, and N. W. Morrell Differential effects of TGF-{beta}1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L919 - L927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. McMurtry, S. Bonnet, X. Wu, J. R.B. Dyck, A. Haromy, K. Hashimoto, and E. D. Michelakis Dichloroacetate Prevents and Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis Circ. Res., October 15, 2004; 95(8): 830 - 840. [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]
|
|
|
|
|
|
J. H. Newman, B. L. Fanburg, S. L. Archer, D. B. Badesch, R. J. Barst, J. G.N. Garcia, P. N. Kao, J. A. Knowles, J. E. Loyd, M. D. McGoon, et al. Pulmonary Arterial Hypertension: Future Directions: Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop Circulation, June 22, 2004; 109(24): 2947 - 2952. [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]
|
|
|
|
 |
|
 A Chaouat, F Coulet, C Favre, G Simonneau, E Weitzenblum, F Soubrier, and M Humbert Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension Thorax, May 1, 2004; 59(5): 446 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rabinovitch The Mouse Through the Looking Glass: A New Door Into the Pathophysiology of Pulmonary Hypertension Circ. Res., April 30, 2004; 94(8): 1001 - 1004. [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]
|
|
|
|
|
|
H. El-Haroun, D. Bradbury, A. Clayton, and A. J. Knox Interleukin-1{beta}, Transforming Growth Factor-{beta}1, and Bradykinin Attenuate Cyclic AMP Production by Human Pulmonary Artery Smooth Muscle Cells in Response to Prostacyclin Analogues and Prostaglandin E2 by Cyclooxygenase-2 Induction and Downregulation of Adenylyl Cyclase Isoforms 1, 2, and 4 Circ. Res., February 20, 2004; 94(3): 353 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Robbins Advancing Therapy for Pulmonary Arterial Hypertension: Can Animal Models Help? Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 5 - 6. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 V. C. Foletta, M. A. Lim, J. Soosairajah, A. P. Kelly, E. G. Stanley, M. Shannon, W. He, S. Das, J. Massague, and O. Bernard Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1 J. Cell Biol., September 15, 2003; 162(6): 1089 - 1098. [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]
|
|
|
|
|
|
S. Sharma Treatment of Pulmonary Arterial Hypertension: A Step Forward Chest, July 1, 2003; 124(1): 8 - 11. [Full Text] [PDF]
|
|
|
|
|
|
C. P. Denton, B. Zheng, L. A. Evans, X. Shi-wen, V. H. Ong, I. Fisher, K. Lazaridis, D. J. Abraham, C. M. Black, and B. de Crombrugghe Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor {beta} (TGF{beta}) Receptor Leads to Paradoxical Activation of TGF{beta} Signaling Pathways with Fibrosis in Transgenic Mice J. Biol. Chem., June 27, 2003; 278(27): 25109 - 25119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 Y. Mitani, A. Mutlu, J. C. Russell, D. N. Brindley, J. DeAlmeida, and M. Rabinovitch Dexfenfluramine protects against pulmonary hypertension in rats J Appl Physiol, November 1, 2002; 93(5): 1770 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Humbert, Z. Deng, G. Simonneau, R.J. Barst, O. Sitbon, M. Wolf, N. Cuervo, K.J. Moore, S.E. Hodge, J.A. Knowles, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives Eur. Respir. J., September 1, 2002; 20(3): 518 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Humbert and R.C. Trembath Genetics of pulmonary hypertension: from bench to bedside Eur. Respir. J., September 1, 2002; 20(3): 741 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nishihara, T. Watabe, T. Imamura, and K. Miyazono Functional Heterogeneity of Bone Morphogenetic Protein Receptor-II Mutants Found in Patients with Primary Pulmonary Hypertension Mol. Biol. Cell, September 1, 2002; 13(9): 3055 - 3063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]
|
|
|
|
|
|
M.M. Hoeper Pulmonary hypertension in collagen vascular disease Eur. Respir. J., March 1, 2002; 19(3): 571 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N Rudarakanchana, R C Trembath, and N W Morrell New insights into the pathogenesis and treatment of primary pulmonary hypertension Thorax, November 1, 2001; 56(11): 888 - 890. [Full Text] [PDF]
|
|
|
|
|
|
C. Atkinson, S. Stewart, P. D. Upton, R. Machado, J. R. Thomson, R. C. Trembath, and N. W. Morrell Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor Circulation, April 9, 2002; 105(14): 1672 - 1678. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||