doi: 10.1161/01.RES.0000128079.89263.68
© 2004 American Heart Association, Inc.
Editorials |
The Mouse Through the Looking Glass
A New Door Into the Pathophysiology of Pulmonary Hypertension
From the Department of Pediatrics, Stanford University, Calif.
Correspondence to Marlene Rabinovitch, MD, Stanford University, Department of Pediatrics, Room 2245B, 269 Campus Drive, Stanford, CA 94305-5168. E-mail marlener{at}stanford.edu
See related article, pages 1109–1114
Key Words: pulmonary hypertension • bone morphogenetic protein receptor • smooth muscle cells • transgenic mouse • hypoxia
Idiopathic pulmonary artery hypertension (IPH) is a rare illness with a poor prognosis. Whereas chronic intravenous prostacyclin relieves some of the symptoms of progressive dyspnea and prolongs survival, most patients ultimately require a lung transplant.1
Newer therapies such as nonintravenously administered prostacyclin derivatives,2,3,4 endothelin receptor blockers,5,6 and, to some extent, phosphodiesterase inhibitors,7 hold some promise as alternatives for intravenous prostacyclin, but current expectation is that, like prostacyclin, they will, at best, retard disease progression, serving as a bridge to transplant rather than as an alternative. The pathological features of IPH are loss of small distal precapillary pulmonary arteries, obliterative changes (plexogenic lesions) in more proximal pulmonary arteries associated with migration and proliferation of smooth muscle cells, and increased extracellular matrix deposition. There is also dysregulation of endothelial cells associated with increased proliferation.8 The mechanism underlying the evolution of these changes is unknown, so there was great interest when 2 groups independently identified a mutation in bone morphogenetic protein receptor 11 (BMP-RII) in 60% of families with IPH.9,10 A BMP-RII mutation also occurs in 20% of sporadic cases of IPH,11 but the biological connection between the mutation and the pathobiology of IPH has been relatively elusive.
Recent studies using pulmonary artery smooth muscle cells from patients with IPH, including those with and without a BMP-RII mutation, showed similar abnormal proliferation in response to agents such as transforming growth factor-ß (TGF-ß) or BMP-2.12 In other studies, pulmonary artery smooth muscle cells were transfected with constructs encoding different mutant forms of BMP-RII expressing aberrant kinase or cytoplasmic domains, and impaired signaling was observed related to alterations in the induction of Smads and p38.13 Specifically, suppression of Smad1/5 and activation of p38 were related to smooth muscle cell proliferation. It is still unknown specifically how these abnormalities in signaling regulate genes that induce smooth muscle cell proliferation or the more complex features associated with obliterative vascular lesions and plexiform changes that are related to aberrant endothelial function, smooth muscle cell migration and abnormal matrix production,14 or sensitivity or resistance to apoptosis.15,16 One possibility it that there is altered function of a transcription factor that binds Smad proteins, such as AML117 (Figure). This is intriguing because we have related AML1 to the induction of an elastase enzyme18 that is pivotal to the progression of pulmonary hypertension in animal models.19 Quite recently, using a yeast 2-hybrid system, mutations in the cytoplasmic tail of BMP-RII have been linked to altered interaction with a microtubule-associated protein, but the significance of this abnormality remains to be determined.20
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It would therefore be valuable to create a mouse in which the vascular pathology related to the mutation could be evaluated. Deletion of BMP-RII in the mouse is lethal in embryonic life,21 and the heterozygote has a relatively unremarkable phenotype. So it is with great interest that we read in this issue of Circulation Research a report from the laboratory of Dr David Rodman22 describing the development of pulmonary hypertension in a mouse induced by overexpressing the human BMP-RII mutation in vascular smooth muscle cells in the postnatal period. This is achieved by driving expression of the BMP-RII mutation with the SM22 vascular smooth muscle-specific promoter under the regulation of tetracycline. The mice described have pulmonary hypertension in room air and more severe pulmonary hypertension than control mice in Denver altitude or with hypoxia. This more severe pulmonary hypertension is associated with a relatively modest increase in the number of muscularized distal vessels and in the hypertrophy of the more proximal pulmonary arteries. Although these features do not recapitulate the full pathology found in IPH patients, they are common to all forms of pulmonary hypertension regardless of etiology. Thus, the authors of this report are able, for the first time, to link the mutation to the pathobiology of pulmonary hypertension in an intact animal. With the proviso that the mouse and human respond similarly, the report also suggests that there is a link between the early pulmonary arterial changes common to all patients with pulmonary hypertension and the later obliterative changes in IPH. The progression from increased muscularity of pulmonary arteries to obliterative neointimal formation has been observed in pulmonary hypertension associated with congenital heart defects but has not been shown in IPH, perhaps because the changes in the pulmonary circulation are usually very advanced when the clinical diagnosis of IPH is made.
Whereas pulmonary artery endothelial and smooth muscle cells express BMP-RII, it is unknown whether the pathology of IPH is influenced by a mutation in BMP-RII affecting endothelial23 or smooth muscle cells or both.24 This article would implicate smooth muscle cells in the pathobiology of hypertension, but it could be argued that the full-blown pathology of IPH requires abnormal function of endothelial as well as smooth muscle cells. It is also possible that a fibroblast, a progenitor cell,25 or a nonvascular cell expressing BMP-RII plays a critical role in the pathology observed clinically. Thus, it would be interesting to study the phenotype resulting from loss of function of BMP-RII in all cells in the late embryonic or postnatal period when the lethality could be subverted. This could be achieved by tetracycline-regulated loss of gene expression downstream of a nontissue-specific promoter. Alternatively, it is possible that the full-blown phenotype requires expression of the mutation in smooth muscle cells in embryonic life. It is also possible that overexpression of the human mutation will not result in the same end point as replacement of the gene on 1 allele with the mutation. It will therefore be interesting to compare the mouse described in this study to one in which BMP-RII is deleted in all cells in late embryonic or postnatal period, and to one in which BMP-RII is deleted in endothelial or smooth muscle cells throughout fetal life or in the postnatal period. This would involve making a mouse in which flanking the BMP-RII gene with LoxP sites would enable deletion of the gene in a temporal or spatial specific pattern as a result of breeding with a mouse in which the enzyme Cre is regulated by a tissue-specific promoter or in an inducible manner. It will also be of interest to assess the response of the mouse described in this article to other factors known to present risks for the development of pulmonary hypertension, such as appetite suppressants26 and infection or inflammation.27,28,29
Regardless of the model, there is the question of how the mutation leads to the vascular abnormality, in this case, the pulmonary hypertension and increased muscularity of the arteries, and why there appears to be a dissociation between the severity of the hypertension and the mild nature of the changes described. Harvesting smooth muscle cells would be of great value to enable more precise delineation of the interactions between the aberrant BMP-RII and the coreceptor BMP-RI and the pattern of downstream signaling events. Knowing which genes and which transcription factors are involved would be of interest in finding a common pathway that may be abnormal in patients that do not have the BMP-RII mutation. For example, because an increased frequency of polymorphisms causing heightened activity of the serotonin transporter has been implicated in IPH,30 it would be of interest to determine whether BMP-RII influences the activity of the serotonin transporter or whether breeding this BMP-RII mutant mouse with a mouse with serotonin transporter overexpression would result in more severe pulmonary hypertension and vascular disease. It would also be of interest to determine whether other gene products implicated in the pathobiology of pulmonary hypertension, such as elastase, tenascin,19 and Mts1,31 are upregulated when BMP-RII signaling is abnormal; whether there is K channel dysfunction;32,33,33a or whether the induction of these gene products promotes the development of pulmonary vascular disease when BMP-RII is abnormal. These kinds of studies may also resolve the controversy in the literature as to whether under certain circumstances angiopoietin is protective15 or promotes the pathobiology of pulmonary artery hypertension.34
That is, it has been previously shown that decreased K channel function is observed in cells from patients with IPH and is seen in response to pulmonary hypertension producing stimuli such as appetite suppressants and hypoxia.32 Cell culture studies indicate that BMP2 normally causes K channel dependent apoptosis of smooth muscle cells, which may not occur in cells with the BMP-RII mutation.16 Elastase activity19 is induced by plasma factors such as apoA135 and also by stimulation of serotonin receptors.36 Elastase activity can contribute to proliferation by releasing matrix-bound growth factors37 and by upregulating tenascin C, which facilitates phosphorylation of growth factor receptors.38 Elastase-mediated elastin peptide production can also promote migration of smooth muscle cells by increasing production of fibronectin.39,40 Angiopoietin I has been reported to protect against the loss of small vessels that occurs as a result of enodthelial cell apoptosis.15 In contrast, it has also been suggested that angiopoietin induces serotonin release from endothelial cells, and, thus, is responsible for serotonin-mediated smooth muscle cell proliferation.34 How all these factors are linked to BMP-RII in a living animal can be tested in this and other murine models. Thus, the article by West et al from the Rodman laboratory is the first major step toward linking a genetic defect seen in patients with the pathology of pulmonary hypertension in an intact animal and will be enormously useful in determining pathways that are potential targets to prevent and reverse pathology.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Kuhn KP, Byrne DW, Arbogast PG, Doyle TP, Loyd JE, Robbins IM. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003; 167: 580–586.
2. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002; 39: 1496–1502.
3. Hoeper MM, Spiekerkoetter E, Westerkamp V, Gatzke R, Fabel H. Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension. Eur Respir J. 2002; 20: 339–343.
4. McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, Robbins IM, Tapson VF, McGoon MD, Badesch DB, Sigman J, Roscigno R, Blackburn SD, Arneson C, Rubin LJ, Rich S. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003; 41: 293–299.[CrossRef][Medline] [Order article via Infotrieve]
5. Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003; 124: 247–254.
6. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004; 169: 441–447.
7. Bhatia S, Frantz RP, Severson CJ, Durst LA, McGoon MD. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc. 2003; 78: 1207–1213.
8. Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, Tuder RM. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol. 1999; 155: 411–419.
9. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Loyd JE, III, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nature Genetics. 2000; 26: 81–84.[CrossRef][Medline] [Order article via Infotrieve]
10. 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]
11. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA, III, Loyd JE. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. 2001; 345: 319–324.
12. Morrell NW, 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.
13. Rudarakanchana N, Flanagan JA, Chen H, Upton PD, Machado R, Patel D, Trembath RC, Morrell NW. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002; 11: 1517–1525.
14. Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol. 1997; 150: 1349–1360.[Abstract]
15. Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res. 2003; 92: 984–991.
16. 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.Epub 2003 May 09.
17. Jakubowiak A, Pouponnot C, Berguido F, Frank R, Mao S, Massague J, Nimer SD. Inhibition of the transforming growth factor beta 1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. J Biol Chem. 2000; 275: 40282–40287.
18. Wigle DA, Thompson KE, Yablonsky S, Zaidi SH, Coulber C, Jones PL, Rabinovitch M. AML1-like transcription factor induces serine elastase activity in ovine pulmonary artery smooth muscle cells. Circ Res. 1998; 83: 252–263.
19. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. 2000; 6: 698–702.[CrossRef][Medline] [Order article via Infotrieve]
20. Machado RD, Rudarakanchana N, Atkinson C, Flanagan JA, Harrison R, Morrell NW, Trembath RC. 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. 2003; 12: 3277–3286.
21. Beppu H, Kawabata M, Hamamoto T, Chytil A, Minowa O, Noda T, Miyazono K. BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol. 2000; 221: 249–258.[CrossRef][Medline] [Order article via Infotrieve]
22. 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.
23. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Tembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002; 105: 1627–1678.
24. DeCaestecker M, Meyrick B. Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Respir Res. 2001; 2: 193–197.[CrossRef][Medline] [Order article via Infotrieve]
25. Davie NJ, Crossno JT, Jr., Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, Stenmark KR. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol. 2004; 286: L668–78.
26. Abenhaim L, Humbert M. Pulmonary hypertension related to drugs and toxins. Curr Opin Cardiol. 1999; 14: 437–441.[CrossRef][Medline] [Order article via Infotrieve]
27. Balabanian K, Foussat A, Dorfmuller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, Portier A, Marfaing-Koka A, Krzysiek R, Rimaniol AC, Simonneau G, Emilie D, Humbert M. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002; 165: 1419–1425.
28. Martin I, Humbert M, Marfaing-Koka A, Capron F, Wolf M, Meyer D, Simonneau G, Angles-Cano E. Plasminogen activation by blood monocytes and alveolar macrophages in primary pulmonary hypertension. Blood Coagul Fibrinolysis. 2002; 13: 417–422.[CrossRef][Medline] [Order article via Infotrieve]
29. 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.
30. 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]
31. Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol. 2004; 164: 253–262.
32. Weir EK, Reeve HL, Johnson G, Michelakis ED, Nelson DP, Archer SL. A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension. Chest. 1998; 114: S200–4.
33. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JJ, 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.
33. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, Archer SL. In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation. 2003; 107: 2037–2044.
34. 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.
35. Thompson K, Kobayashi J, Childs T, Wigle D, Rabinovitch M. Endothelial and serum factors which include apolipoprotein A1 tether elastin to smooth muscle cells inducing serine elastase activity via tyrosine kinase-mediated transcription and translation. J Cel. Physiol. 1998; 174: 78–89.[CrossRef][Medline] [Order article via Infotrieve]
36. Launay JM, Herve 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]
37. Thompson KE, Rabinovitch M. Human leukocyte elastase mediates release of extracellular matrix-bound bFGF in vascular smooth muscle cell cultures. Mol Biol Cell. 1994; 5 (suppl): 378a.
38. Jones PL, Crack J, Rabinovitch M. Regulation of Tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J. Cell Biol. 1997; 139: 279–293.
39. Hinek A, Molossi S, Rabinovitch M. Functional interplay between interleukin-1 receptor and elastin binding protein regulates fibronectin production in coronary artery smooth muscle cells. Exp Cell Res. 1996; 225: 122–131.[CrossRef][Medline] [Order article via Infotrieve]
40. Mochizuki S, Brassart B, Hinek A. Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells. J Biol Chem. 2002; 277: 44854–44863.
41. Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI, Knaus P. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem. 2002; 277: 5330–5338.
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