This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yuan, J. X.-J. Articles by Rubin, L. J. Search for Related Content PubMed PubMed Citation Articles by Yuan, J. X.-J. Articles by Rubin, L. J. Related Collections Pulmonary circulation and disease Related Article

(Circulation. 2005;111:534-538.)
© 2005 American Heart Association, Inc.

Editorial

Pathogenesis of Pulmonary Arterial Hypertension

The Need for Multiple Hits

Jason X.-J. Yuan, MD, PhD; Lewis J. Rubin, MD

From the Department of Medicine, School of Medicine, University of California-San Diego, La Jolla.

Correspondence to Dr Lewis J. Rubin, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California-San Diego, La Jolla, CA 92037-7381. E-mail ljrubin{at}ucsd.edu

Key Words: Editorials • hypertension, pulmonary • genes • heart diseases, pulmonary

Pulmonary hypertension can be classified into 4 categories: pulmonary arterial hypertension (PAH), pulmonary venous hypertension, pulmonary hypertension associated with hypoxemia, and pulmonary hypertension due to chronic thrombotic or embolic disease. PAH is a progressive and often fatal condition that predominantly affects women. Approximately 10% of patients diagnosed with PAH without a demonstrable cause have a family history of the disease and are referred to as having familial PAH (FPAH), whereas the remainder are classified as having idiopathic PAH (IPAH).

See p 607

Regardless of the initial pathogenic trigger, the elevated pulmonary arterial pressure and vascular resistance in patients with FPAH and IPAH are primarily caused by sustained pulmonary vasoconstriction, lumen obliteration of small- and medium-sized arteries and arterioles in association with the formation of plexiform lesions and in situ thrombosis, and concentric thickening of pulmonary arteries resulting from intimal fibrosis, and medial hypertrophy resulting from excessive proliferation of smooth muscle cells.¹ The plexiform lesion, a histological hallmark of FPAH and IPAH, has been demonstrated to result from monoclonal proliferation of endothelial cells, migration and proliferation of smooth muscle cells, and accumulation of circulating cells (eg, macrophages, endothelial progenitor cells).^1,2 These observations suggest that the pulmonary vasculature in FPAH and IPAH patients is phenotypically different from that in normal subjects because of inheritable or acquired mutations (or polymorphisms) of certain genes that are specifically involved in regulating proliferation, apoptosis, and differentiation in pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs).

The pathogenesis of PAH remains incompletely understood; however, heterozygous mutations of the bone morphogenetic protein (BMP) receptor type II (BMP-RII) gene (BMPR2) have been implicated in the development of both FPAH and IPAH.^3,4 BMPR2 mutations, which are distributed in the 13 coding exons of the gene and its flanking intronic sequences, have been identified in 40% of FPAH patients and 15% of IPAH patients. Because the mutant alleles are typically of low penetrance, loss of the wild-type allele as a result of somatic mutations in cells responsible for the plexiform lesion, monoclonal endothelial cell proliferation, and concentric medial hypertrophy may contribute to the onset and progression of IPAH.^5,6 In other words, as indicated by Machado et al⁶ in this issue of Circulation, "FPAH and BMPR2 mutation–positive IPAH might follow the classic ‘2-hit’ model of tumorigenesis and...inactivation of the remaining wild-type BMPR2 allele might be one of the somatic mutations necessary to precipitate disease."

Using polymerase chain reaction analysis, Yeager et al⁵ demonstrated microsatellite instability within the transforming growth factor-ß (TGF-ß) receptor type II (TGF-ß-RII) gene, hMSH2 mismatch repair gene, and Bax (a proapoptotic protein) gene in PAECs isolated from plexiform lesions of severe IPAH patients but not in cells of FPAH patients or lung tissues of normal subjects.⁵ The study by Machado et al⁶ in 7 white patients diagnosed with FPAH (ie, at least 1 family member has the same disease in addition to the patient) provides compelling evidence that microsatellite instability is not common in FPAH and that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers (or loss of heterozygosity) does not contribute to the onset and progression of FPAH.⁶ Therefore, mutations (or polymorphisms) in other genes and altered functions and activities of other gene products may be required as a "trigger" for or "contributor" to the development of the disease. In other words, the onset and progression of PAH, or the histological and functional phenotype of plexogenic pulmonary arteriopathy, require multiple "hits" in BMPR2 mutation carriers and in individuals without BMPR2 mutations but with mutations and abnormalities in other genes and gene products. These hypotheses are further supported by the following recent observations: (1) Transgenic mice expressing a dominant-negative BMPR2 gene in smooth muscle and the heterozygous BMPR2^+/– and BMPR1a^+/– knockout mice develop only mild pulmonary hypertension,^7–9 whereas most FPAH and IPAH patients have severe pulmonary hypertension; (2) mutations or polymorphisms in other genes have been identified and linked to IPAH,¹⁰ such as serotonin receptor (HTR2B) and transporter (SLC6A4),^11,12 K⁺ (KCNA5) and Ca²⁺ (TRPC6) channels,^13–15 and angiopoietin-1 (ANGPT1)¹⁶; and (3) the development of PAH is linked to exogenous factors such as viral and bacterial infection¹⁷ and anorexigen intake.¹ Therefore, the triggers for the onset and the contributors to the progression of PAH in individuals with genetic predispositions (eg, germline mutations or polymorphisms in BMPR2 and other genes) may be genetic (eg, combination of mutations in various genes such as HTR2B, SLC6A4, KCNA5, TRPC6, and ANGPT1), environmental, or acquired factors (eg, viral and bacterial infection, anorexigen intake), or all 3 (Figure).

View larger version (74K): [in this window] [in a new window]   Schematic depicting the potential "hits" involved in the development of PAH. A rise in [Ca2+]cyt in PASMCs (due to decreased Kv channel activity (1) and membrane depolarization, which opens voltage-dependent Ca2+ channels [VDCC]; upregulated TRPC channels that participate in forming receptor- [ROC] and store-operated [SOC] Ca2+ channels (2); and upregulated membrane receptors [eg, serotonin, endothelin, or leukotriene receptors] (3) and their downstream signaling cascades) causes pulmonary vasoconstriction, stimulates PASMC proliferation, and inhibits the BMP-signaling pathway that leads to antiproliferative and proapoptotic effects on PASMCs. Dysfunction of BMP signaling due to BMPR2 mutation and BMP-RII/BMP-RI downregulation (4) and inhibition of Kv channel function and expression (1) attenuate PASMC apoptosis and promote PASMC proliferation. Increased angiopoietin-1 (Ang-1) synthesis and release (5) from PASMCs enhance 5-HT production and downregulate BMP-RIa in PAEC and further enhance PASMC contraction and proliferation, whereas inhibited nitric oxide and prostacyclin (PGI2) synthesis (6) in PAECs would attenuate the endothelium-derived relaxing effect on pulmonary arteries and promote sustained vasoconstriction and PASMC proliferation. Increased activity and expression of the 5-HT transporter (5-HTT) (7) would serve as an additional pathway to stimulate PASMC growth via the mitogen-activated protein kinase (MAPK) pathway. Furthermore, exogenous viral and bacterial infection and inflammation (8) may contribute to vasoconstriction and vascular medial hypertrophy in patients with mutations in multiple genes or with "susceptible predispositions" in these pathways. In addition, a variety of splicing factors, transcription factors, protein kinases, extracellular metalloproteinases, and circulating growth factors would serve as the so-called "hits" to mediate the phenotypical transition of normal cells to contractive or hypertrophied cells and to maintain the progression of PAH. SR indicates sarcoplasmic reticulum; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PLC, phospholipase C; PKC, protein kinase C; GPCR, G protein coupled receptor; RTK, receptor tyrosine kinase, PDGF, platelet-derived growth factor; ROS, reactive oxygen species; and AVD, apoptotic volume decrease.

BMPs, which belong to the TGF-ß superfamily, are synthesized and secreted from a variety of cell types, including PASMCs and PAECs. Signal transduction of BMP-mediated effects in the pulmonary vasculature involves homomeric or heteromeric dimerization of the BMP receptors (BMP-RIa, -RIb, and -RII) and activation (or phosphorylation) of the downstream signaling proteins, Smads (mothers against decapentaplegic proteins). In the absence of BMP ligands, both homomeric and heterogenous BMP receptors (BMP-RIa, BMP-RIb, and BMP-RII) are found in the surface membrane of living cells. Binding of BMP ligands to either of the BMP receptors (BMP-RIa, -RIb, or -RII) induces or augments heterodimerization of BMP-RI and BMP-RII. The ligand/receptor complex is required for activating the BMP-RI kinase.¹⁸

The activated cytoplasmic kinase of BMP-RI then phosphorylates the receptor-activated Smad (R-Smad) proteins (eg, Smad-3, -5, and -8), which then dimerize with co-Smad (eg, Smad-4). The R-Smad and co-Smad complex then translocates into the nucleus to regulate transcription of the target genes that contain the Smad binding sequence (5'-CAGAC-3' and 5'-GTCTG-3') in their promoter. In addition to the R-Smads and co-Smads, humans also express the antagonistic Smads, including Smad-6 and -7, which mediate negative feedback within TGF-ß/BMP signaling pathways and regulatory inputs from other pathways. The antagonistic Smads serve as an R-Smad decoy to compete for the activated tyrosine kinase and therefore to inhibit activation of R-Smads. Smad-6 is an antagonistic Smad that preferentially inhibits BMP signaling (ie, activation of Smad-1/-5/-8). Among the Smad-responsive genes (ie, the genes containing the Smad binding sequences in their promoters), many encode proteins that are required for arresting cell growth and inducing apoptosis (Figure).¹⁸

In addition to activating gene transcription by binding onto the Smad binding sequence in the promoter, increased Smads in the nucleus can also form heterogenous polymers with corepressors, such as the homeodomain protein TGIF and the 2 related proteins c-Ski and SnoN, to induce repression of the transcription of target genes. An additional inhibitor of Smads is the Smad-interacting protein 1 (SIP1), a zinc finger/homeodomain protein that interacts with Smad-1 and -5 in mammalian cells and inhibits BMP-mediated effects.¹⁸ Therefore, BMP-mediated activation and translocation of Smads can exert both augmenting and inhibitory effects on gene transcription, depending on cell types and other transcription factors involved in the signal transduction cascade.

Increased Smads in the nucleus can also form heterogenous polymers with other transcription factors (eg, AP-1) to mediate antiproliferative and proapoptotic effects on a variety of cell types. Furthermore, Smad proteins have been reported to interact with calmodulin, a Ca²⁺-sensitive protein in the cytosol. Overexpression of calmodulin inhibits Smad activation and attenuates the response of BMP signal transduction, suggesting that a rise in [Ca²⁺]_cyt may exert an inhibitory effect on the BMP signaling pathway by activating calmodulin and attenuating BMP-mediated antiproliferative or proapoptotic effects on human PASMCs.

In cells isolated from normal subjects, BMPs inhibit proliferation in PASMCs,¹⁹ induce apoptosis in PASMCs,²⁰ and enhance survival in PAECs and endothelial progenitor cells.²¹ The BMP-mediated apoptosis in normal PASMCs appears to be at least partially due to downregulation of Bcl-2, an antiapoptotic protein.²⁰ The antiproliferative and proapoptotic effects of BMPs in normal PASMCs would lead to a well-maintained balance of the proliferation/apoptosis ratio and to maintenance of the thin pulmonary vascular wall. The antiapoptotic effect of BMPs in normal PAECs would protect endothelial integrity, prevent the "leakage" of circulating growth factors to the media (for stimulating PASMC growth), and enhance endothelium-dependent vasodilation. In PASMCs from IPAH patients, the antiproliferative effect of BMPs is converted to proliferative¹⁹ and the proapoptotic effect is significantly attenuated,²⁰ whereas in PAECs from IPAH patients, the antiapoptotic or survival effect of BMPs is converted to proapoptotic.²¹ The reversed effects of BMPs on PASMCs and PAECs in IPAH patients, because of unknown phenotypical changes, may play an important pathogenic role in pulmonary vascular remodeling and ultimately in pulmonary hypertension.

As mentioned earlier, increased PASMC contraction (resulting from elevated [Ca²⁺]_cyt or enhanced Ca²⁺ sensitivity of contractile proteins), increased PASMC proliferation and inhibited PASMC apoptosis, monoclonal PAEC proliferation, and endothelial injury all are involved in the development of sustained pulmonary vasoconstriction, lumen obliteration of small pulmonary arteries with plexiform lesions, and pulmonary vascular wall thickening due to medial hypertrophy. In addition to BMP ligands and the Smad signaling pathway, many other ligands, receptors, and signal transduction cascades are involved in regulating contraction, migration, proliferation, differentiation, and apoptosis of PASMCs and PAECs. Indeed, it was recently demonstrated that upregulated 5-HT receptors and transporters^11,12 and increased circulating levels of 5-HT (serotonin), upregulated canonical transient receptor potential channels and downregulated Kv channels,^13–15 upregulated angiopoietin-1 and downregulated BMPR-Ia,¹⁶ and imbalanced prostacyclin/thromboxane A₂ or nitric oxide/endothelin-1 ratio^22,23 are involved in the development of sustained pulmonary vasoconstriction and vascular remodeling in IPAH patients (Figure). Furthermore, both loss-of-function (eg, KCNA5) and gain-of-function (eg, SERT) mutations^12,14 in these genes also have been identified in patients with IPAH and linked to the development of the disease. In addition, PAH occurs in the settings of scleroderma, viral hepatitis and other forms of chronic liver disease, and HIV infection, which suggests that triggers for these diseases also may serve as causes for the onset and progression of PAH.

Extensive in vivo and in vitro experiments suggest that the onset of PAH is caused by mutations of multiple genes (either loss-of-function or gain-of-function mutations) and by abnormalities in multiple proteins and signal transduction cascades that are important in maintaining a normal phenotype of PASMCs and PAECs. After the onset of PAH or the initial stage of "pathogenic" phenotypical changes in PASMCs and PAECs, the progression of PAH would be initiated and maintained by the distinct response of the phenotypically changed PASMCs/PAECs to mitogenic agonists and apoptotic inducers. In other words, the PASMCs and PAECs from IPAH patients undergo significant phenotypical changes after the initial transition from a normal phenotype to a "misguided" phenotype, which would then alter their "normal" responses to circulating or locally secreted agonists, growth factors, and apoptosis inducers. The phenotypical changes of PASMCs and PAECs, for example, convert the antiproliferative effects of BMPs (and other proteins and agents) on PASMCs to proliferative effects. Via cDNA microarray experiments, we recently found that in vitro treatment of PASMCs with BMP-2 oppositely regulated mRNA expression in >1000 genes.

In summary, mutations of BMPR2 may serve as a predisposition that increases the susceptibility of the mutant BMPR2 carrier to develop PAH in the presence of various endogenous abnormalities of other genes and gene products and in the presence of exogenous stimuli (eg, viral and bacterial infection, anorexigen intake, chronic exposure to hypoxia). The loss-of-function mutations in BMPR2 or dysfunction of BMP receptors and their downstream signal transduction by Smad proteins appear to be insufficient alone to initiate the disease process. A combination of multiple genetic defects and multiple signal transduction abnormalities in PASMCs and PAECs is required for the pathogenesis of FPAH and IPAH. Furthermore, the onset and progression of PAH may be caused by distinct mechanisms. The onset is likely a transition (eg, dedifferentiation or transdifferentiation) of PASMCs and PAECs from a normal to a "pathogenic" or "misguided" phenotype, whereas the progression is sustained by one of the following abnormalities: cellular factors that create a proliferative, antiapoptotic, and vasoconstrictive milieu; circulating factors that promote a proliferative, antiapoptotic, and vasoconstrictive milieu; and genetic and molecular signaling factors that promote gene transcription and a cellular synthetic cycle, thereby promoting a proliferative, antiapoptotic, and vasoconstrictive milieu. Although it is clear that platelets, fibroblasts, and circulating cells are involved in the progression of PAH, the phenotypical change of PASMCs and PAECs resulting from multiple genetic and acquired defects is probably the major cause for the onset of the disease. Accordingly, future efforts directed at developing effective therapeutic strategies for PAH should target multiple genes, gene products, and signal transduction pathways.

	Acknowledgments

 
This work is supported by the National Institutes of Health grants HL 64945, HL 54043, HL 66012, and HL 69758. The authors wish to acknowledge the investigators whose work could not be included in the Figure and cited in the editorial because of space limitations.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

Top References

 

1. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003; 361: 1533–1544.[CrossRef][Medline] [Order article via Infotrieve]
   
2. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998; 101: 927–934.[Medline] [Order article via Infotrieve]
   
3. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. 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.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000; 26: 81–84.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis within plexiform lesions in primary pulmonary hypertension. Circ Res. 2001; 88: e2–e11.[Medline] [Order article via Infotrieve]
   
6. Machado RD, James V, Southwood M, Harrison RE, Atkinson C, Stewart S, Morrell NW, Trembath RC, Aldred MA. Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation. 2005; 111: 607–613.[Abstract/Free Full Text]
   
7. West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, Rodman DM. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res. 2004; 94: 1109–1114.[Abstract/Free Full Text]
   
8. Beppu H, Ishinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD. 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. 2004; 287: L1241–L1247.[Abstract/Free Full Text]
   
9. El-Bizri N, Wang L, Merkinger SL, Desai K, Blair Rountree R. Transgenic mice with arterial smooth muscle cell-specific conditional deletion of the bone morphogenetic protein type IA receptor (BMPRIA/ALK3) are hyporesponsive to hypoxia. Circulation. 2004; 110 (suppl III): III-132.
   
10. Rindermann M, Grunig E, von Hippel A, Koehler R, Miltenberger-Miltenyi G, Mereles D, Arnold K, Pauciulo M, Nichols W, Olschewski H, Hoeper MM, Winkler J, Katus HA, Kübler W, Bartram CR, Janssen B. Primary pulmonary hypertension may be a heterogenous disease with a second locus on chromosome 2q31. J Am Coll Cardiol. 2003; 41: 2237–2244.[Abstract/Free Full Text]
    
11. Launay J-M, Hervé P, Peoc’h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med. 2002; 8: 1129–1135.[CrossRef][Medline] [Order article via Infotrieve]
    
12. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001; 108: 1141–1150.[CrossRef][Medline] [Order article via Infotrieve]
    
13. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage-gated K⁺ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998; 98: 1400–1406.[Abstract/Free Full Text]
    
14. Remillard CV, Tigno DD, Rana BK, Conger D, Nicholson A, Rubin LJ, O’Connor DT, Yuan JX. Novel SNPs in KCNA5 gene from patients with idiopathic pulmonary hypertension. Circulation. 2004; 110 (suppl III): III-20.
    
15. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2004; 101: 13861–13866.[Abstract/Free Full Text]
    
16. Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan JX, Deutsch R, Jamieson SW, Thistlethwaite PA. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med. 2003; 348: 500–509.[Abstract/Free Full Text]
    
17. Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003; 349: 1113–1122.[Abstract/Free Full Text]
    
18. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signaling. Nature. 2003; 425: 577–584.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Morrell N, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation. 2001; 104: 790–795.[Abstract/Free Full Text]
    
20. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003; 285: L740–L754.[Abstract/Free Full Text]
    
21. Teichert-Kuliszewska K, Kuliszewski MA, Karoubi G, Kang X, Courtman DW. BMPR-2 signaling promotes pulmonary arterial endothelial cell survival: Implications for the pathogenesis of primary pulmonary hypertension. Circulation. 2004; 110 (suppl III): III-132.
    
22. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992; 327: 70–75.[Abstract]
    
23. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995; 333: 214–221.[Abstract/Free Full Text]
    

Related Article:

Investigation of Second Genetic Hits at the BMPR2 Locus as a Modulator of Disease Progression in Familial Pulmonary Arterial Hypertension

Rajiv D. Machado, Victoria James, Mark Southwood, Rachel E. Harrison, Carl Atkinson, Susan Stewart, Nicholas W. Morrell, Richard C. Trembath, and Micheala A. Aldred
Circulation 2005 111: 607-613. [Abstract] [Full Text]

This article has been cited by other articles:

				L. J. Rubin BMPR2 Mutation and Outcome in Pulmonary Arterial Hypertension: Clinical Relevance to Physicians and Patients Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1300 - 1301. [Full Text] [PDF]

				B. Sztrymf, F. Coulet, B. Girerd, A. Yaici, X. Jais, O. Sitbon, D. Montani, R. Souza, G. Simonneau, F. Soubrier, et al. Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1377 - 1383. [Abstract] [Full Text] [PDF]

				C. Lafaras, E. Mandala, E. Verrou, D. Platogiannis, N. Barbetakis, T. Bischiniotis, and K. Zervas Nonthromboembolic pulmonary hypertension in multiple myeloma, after thalidomide treatment: A pilot study Ann. Onc., May 13, 2008; (2008) mdn287v1. [Abstract] [Full Text] [PDF]

				M. Humbert Update in Pulmonary Arterial Hypertension 2007 Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 574 - 579. [Full Text] [PDF]

				R. Souza, M. Humbert, B. Sztrymf, X. Jais, A. Yaici, J. Le Pavec, F. Parent, P. Herve, F. Soubrier, O. Sitbon, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases Eur. Respir. J., February 1, 2008; 31(2): 343 - 348. [Abstract] [Full Text] [PDF]

				D. O. Schwenke, T. Tokudome, M. Shirai, H. Hosoda, T. Horio, I. Kishimoto, and K. Kangawa Exogenous Ghrelin Attenuates the Progression of Chronic Hypoxia-Induced Pulmonary Hypertension in Conscious Rats Endocrinology, January 1, 2008; 149(1): 237 - 244. [Abstract] [Full Text] [PDF]

				I. R. Henkens, K. T. B. Mouchaers, H. W. Vliegen, W. J. van der Laarse, C. A. Swenne, A. C. Maan, H. H. M. Draisma, I. Schalij, E. E. van der Wall, M. J. Schalij, et al. Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1300 - H1307. [Abstract] [Full Text] [PDF]

				P. B. Sehgal and S. Mukhopadhyay Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs? Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H77 - H85. [Abstract] [Full Text] [PDF]

				P. B. Sehgal, S. Mukhopadhyay, F. Xu, K. Patel, and M. Shah Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1526 - L1542. [Abstract] [Full Text] [PDF]

				S. I. Said, S. A. Hamidi, K. G. Dickman, A. M. Szema, S. Lyubsky, R. Z. Lin, Y.-P. Jiang, J. J. Chen, J. A. Waschek, and S. Kort Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene Circulation, March 13, 2007; 115(10): 1260 - 1268. [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]

				S. I. Said Mediators and modulators of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L547 - L558. [Abstract] [Full Text] [PDF]

				V. V. McLaughlin and M. D. McGoon Pulmonary Arterial Hypertension Circulation, September 26, 2006; 114(13): 1417 - 1431. [Full Text] [PDF]

				O. Sanchez, O. Sitbon, X. Jais, G. Simonneau, and M. Humbert Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest, July 1, 2006; 130(1): 182 - 189. [Abstract] [Full Text] [PDF]

				N. P.J. Brindle, P. Saharinen, and K. Alitalo Signaling and Functions of Angiopoietin-1 in Vascular Protection Circ. Res., April 28, 2006; 98(8): 1014 - 1023. [Abstract] [Full Text] [PDF]

				A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]

				P. Pokreisz, I. Fleming, L. Kiss, E. Barbosa-Sicard, B. Fisslthaler, J. R. Falck, B. D. Hammock, I.-H. Kim, Z. Szelid, P. Vermeersch, et al. Cytochrome P450 Epoxygenase Gene Function in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling Hypertension, April 1, 2006; 47(4): 762 - 770. [Abstract] [Full Text] [PDF]

				L. J. Rubin Pulmonary arterial hypertension. Proceedings of the ATS, January 1, 2006; 3(1): 111 - 115. [Abstract] [Full Text] [PDF]

				W. K. P. Wong, J. A. Knowles, and J. H. Morse Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src: Implication for a Role in Pulmonary Arterial Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 438 - 446. [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]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yuan, J. X.-J. Articles by Rubin, L. J. Search for Related Content PubMed PubMed Citation Articles by Yuan, J. X.-J. Articles by Rubin, L. J. Related Collections Pulmonary circulation and disease Related Article