Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension

Respiration

Volumn 85, Issue 5, 2013, Pages 355-364

  Farkas, Laszlo ^a   Kolb, Martin ^b  

^a VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

Progenitor cells; Pulmonary arterial hypertension; Stem cells; Vascular regeneration

Indexed keywords

ADVENTITIA; ANGIOGENESIS; BONE MARROW DERIVED MESENCHYMAL STEM CELL; ENDOTHELIAL PROGENITOR CELL; GENE TRANSFER; GENETIC MANIPULATION; HEMATOPOIETIC STEM CELL; HUMAN; LUNG CIRCULATION; NONHUMAN; PH; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; TUNICA MEDIA; VASCULAR REMODELING; VASCULAR SURGERY;

EID: 84876503247     PISSN: 00257931     EISSN: 14230356     Source Type: Journal    
DOI: 10.1159/000350177     Document Type: Review

References (116)

1. Erzurum S, Rounds SI, Stevens T, Aldred M, Aliotta J, Archer SL, Asosingh K, Balaban R, Bauer N, Bhattacharya J, Bogaard H, Choudhary G, Dorn GW II, Dweik R, Fagan K, Fallon M, Finkel T, Geraci M, Gladwin MT, Hassoun PM, Humbert M, Kaminski N, Kawut SM, Loscalzo J, McDonald D, McMurtry IF, Newman J, Nicolls M, Rabinovitch M, Shizuru J, Oka M, Polgar P, Rodman D, Schumacker P, Stenmark K, Tuder R, Voelkel N, Sullivan E, Weinshilboum R, Yoder MC, Zhao Y, Gail D, Moore TM. Strategic plan for lung vascular research: an NHLBI-ORDR Workshop Report. Am J Respir Crit Care Med 2010; 182: 1554-1562.
2. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing Z-C, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S43-S54.
3. International PPH Consortium, 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. Nat Genet 2000; 26: 81-84.
4. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012; 122: 4306-4313.
5. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 261-272.
6. Sakao S, Tatsumi K, Voelkel NF. Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2010; 43: 629-634.
7. Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, Tuder RM. Threedimensional 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.
8. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S3-S9.
9. Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration 2013; 85: 3-10.
10. Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 2011; 8: 223-272.
11. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967.
12. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA. Redefining endo thelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007; 109: 1801-1809.
13. Asosingh K, Aldred MA, Vasanji A, Drazba J, Sharp J, Farver C, Comhair SAA, Xu W, Licina L, Huang L, Anand-Apte B, Yoder MC, Tuder RM, Erzurum SC. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am J Pathol 2008; 172: 615-627.
14. Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LSG, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, Morrell NW. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 2009; 180: 780-787.
15. Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, Weil J, Reichenspurner H, Kilic N, Ergun S. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 2006; 133: 1543-1551.
16. Ingram DA, Mead LE, Moore DB, Woodard W, Fenoglio A, Yoder MC. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 2005; 105: 2783-2786.
17. Alvarez DF, Huang L, King JA, ElZarrad MK, Yoder MC, Stevens T. Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity. Am J Physiol Lung Cell Mol Physiol 2008; 294: L419-L430.
18. Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogorek B, Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G, Haley KJ, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella MA, Loscalzo J, Anversa P. Evidence for human lung stem cells. N Engl J Med 2011; 364: 1795-1806.
19. Fang S, Wei J, Pentinmikko N, Leinonen H, Salven P. Generation of functional blood vessels from a single c-kit+ adult vascular endothelial stem cell. PLoS Biol 2012; 10:e1001407.
20. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147.
21. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25: 2739-2749.
22. Bhatia R, Hare JM. Mesenchymal stem cells: future source for reparative medicine. Congest Heart Fail 2005; 11: 87-93.
23. Prockop DJ, Youn Oh J. Mesenchymal stem/ stromal cells (MSCs): role as guardians of inflammation. Mol Ther 2012; 20: 14-20.
24. Ntolios P, Janes SM. Mesenchymal stem cell therapy for lung diseases: oasis or mirage. Respiration 2013; 85: 279-280.
25. Lama VN, Smith L, Badri L, Flint A, Andrei A-C, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M, Pinsky DJ, Martinez FJ, Thannickal VJ. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007; 117: 989-996.
26. Firth AL, Yao W, Ogawa A, Madani MM, Lin GY, Yuan JX-J: Multipotent mesenchymal progenitor cells are present in endarterectomized tissues from patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Cell Physiol 2010; 298:C1217-C1225.
27. Loges S, Fehse B, Brockmann MA, Lamszus K, Butzal M, Guckenbiehl M, Schuch G, Ergun S, Fischer U, Zander AR, Hossfeld DK, Fiedler W, Gehling UM. Identification of the adult human hemangioblast. Stem Cells Dev 2004; 13: 229-242.
28. Prindull G. Hemangioblasts representing a functional endothelio-hematopoietic entity in ontogeny, postnatal life, and CML neovasculogenesis. Stem Cell Rev 2005; 1: 277-284.
29. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, MacArthur BD, Lira SA, Scadden DT, Ma'ayan A, Enikolopov GN, Frenette PS. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829-834.
30. Farha S, Asosingh K, Xu W, Sharp J, George D, Comhair S, Park M, Tang WHW, Loyd JE, Theil K, Tubbs R, Hsi E, Lichtin A, Erzurum SC. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities. Blood 2011; 117: 3485-3493.
31. Gambaryan N, Perros F, Montani D, Cohen-Kaminsky S, Mazmanian M, Renaud JF, Simonneau G, Lombet A, Humbert M. Targeting of c-kit+ haematopoietic progenitor cells prevents hypoxic pulmonary hypertension. Eur Respir J 2011; 37: 1392-1399.
32. Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, Weil J, Reichenspurner H, Kilic N, Ergun S. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 2006; 133: 1543-1551.
33. Montani D, Perros F, Gambaryan N, Girerd B, Dorfmuller P, Price LC, Huertas A, Hammad H, Lambrecht B, Simonneau G, Launay J-M, Cohen-Kaminsky S, Humbert M. C-kitpositive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2011; 184: 116-123.
34. Rai PR, Cool CD, King JAC, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 178: 558-564.
35. Asosingh K, Farha S, Lichtin A, Graham B, George D, Aldred M, Hazen SL, Loyd J, Tu-der R, Erzurum SC. Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension. Blood 2012; 120: 1218-1227.
36. Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, Strieter RM. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 2007; 353: 104-108.
37. Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, O'Byrne PM, Strieter RM, Kolb M. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 588-594.
38. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004; 114: 438-446.
39. Nikam VS, Schermuly RT, Dumitrascu R, Weissmann N, Kwapiszewska G, Morrell N, Klepetko W, Fink L, Seeger W, Voswinckel R. Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension. Eur Respir J 2010; 36: 1302-1314.
40. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006; 168: 659-669.
41. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease?. J Clin Invest 2000; 106: 733-738.
42. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010; 121: 2747-2754.
43. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012; 302: L363-L369.
44. Gomez-Arroyo JG, Saleem SJ, Mizuno S, Syded AA, Bogaard HJ, Abbate A, Taraseviciene-Stewart L, Sung Y, Kraskauskas D, Farkas D, Conrad DH, Nicolls MR, Voelkel NF. A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects. Am J Physiol Lung Cell Mol Physiol 2012; 302:L977-L991.
45. Tzouvelekis A, Ntolios P, Bouros D. Stem cell treatment for chronic lung diseases. Respiration 2013; 85: 179-192.
46. Bouros D, Laurent G. Regenerative medicine and stem cells: Prometheus revisited. Respiration 2013; 85: 1-2.
47. Furze RC, Rankin SM. Neutrophil mobilization and clearance in the bone marrow. Immunology 2008; 125: 281-288.
48. Azoulay E, Attalah H, Yang K, Jouault H, Schlemmer B, Brun-Buisson C, Brochard L, Harf A, Delclaux C. Exacerbation by granulocyte colony-stimulating factor of prior acute lung injury: implication of neutrophils. Crit Care Med 2002; 30: 2115-2122.
49. Greenbaum AM, Link DC. Mechanisms of GCSF-mediated hematopoietic stem and progenitor mobilization. Leukemia 2011; 25: 211-217.
50. Baldo MP, Davel AP, Damas-Souza DM, Nicoletti-Carvalho JE, Bordin S, Carvalho HF, Rodrigues SL, Rossoni LV, Mill JG. The antiapoptotic effect of granulocyte colony-stimulating factor reduces infarct size and prevents heart failure development in rats. Cell Physiol Biochem 2011; 28: 33-40.
51. Baldo MP, Davel AP, Nicoletti-Carvalho JE, Bordin S, Rossoni LV, Mill JG. Granulocyte colony-stimulating factor reduces mortality by suppressing ventricular arrhythmias in acute phase of myocardial infarction in rats. J Cardiovasc Pharmacol 2008; 52: 375-380.
52. Maruyama H, Watanabe S, Kimura T, Liang J, Nagasawa T, Onodera M, Aonuma K, Yamaguchi I. Granulocyte colony-stimulating factor prevents progression of monocrotaline-induced pulmonary arterial hypertension in rats. Circ J 2007; 71: 138-143.
53. Azoulay E, Eddahibi S, Marcos E, Levame M, Harf A, Schlemmer B, Adnot S, Delclaux C. Granulocyte colony-stimulating factor enhances alpha-naphthylthiourea-induced pulmonary hypertension. J Appl Physiol 2003; 94: 2027-2033.
54. Xie J, Hu D, Niu L, Qu S, Wang S, Liu S. Mesenchymal stem cells attenuate vascular remodeling in monocrotaline-induced pulmonary hypertension rats. J Huazhong Univ Sci Technolog Med Sci 2012; 32: 810-817.
55. Zhang ZH, Lu Y, Luan Y, Zhao JJ. Effect of bone marrow mesenchymal stem cells on experimental pulmonary arterial hypertension. Exp Ther Med 2012; 4: 839-843.
56. Jiang L, Song XH, Liu P, Zeng CL, Huang ZS, Zhu LJ, Jiang YZ, Ouyang HW, Hu H. Platelet-mediated mesenchymal stem cells homing to the lung reduces monocrotaline-induced rat pulmonary hypertension. Cell Transplant 2012;21:1463-1475.
57. Luan Y, Zhang X, Kong F, Cheng GH, Qi TG, Zhang ZH. Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism. Int Immunopharmacol 2012; 14: 432-437.
58. Liu K, Liu R, Cao G, Sun H, Wang X, Wu S. Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models. Stem Cells Dev 2011; 20: 1001-1010.
59. Hansmann G, Fernandez-Gonzalez A, Aslam M, Vitali SH, Martin T, Mitsialis SA, Kourembanas S. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2012; 2: 170-181.
60. Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, Kadowitz PJ. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007; 292:H1120-H1128.
61. Rochefort GY, Vaudin P, Bonnet N, Pages JC, Domenech J, Charbord P, Eder V. Influence of hypoxia on the domiciliation of mesenchymal stem cells after infusion into rats: possibilities of targeting pulmonary artery remodeling via cells therapies?. Respir Res 2005; 6: 125.
62. Zhang Y, Liao S, Yang M, Liang X, Poon MW, Wong CY, Wang J, Zhou Z, Cheong SK, Lee CN, Tse HF, Lian Q. Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplant 2012; 21: 2225-2239.
63. Luan Y, Zhang ZH, Wei DE, Lu Y, Wang YB. Effects of autologous bone marrow mononuclear cells implantation in canine model of pulmonary hypertension. Circ J 2012; 76: 977-985.
64. Spees JL, Whitney MJ, Sullivan DE, Lasky JA, Laboy M, Ylostalo J, Prockop DJ. Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J 2008; 22: 1226-1236.
65. Takahashi M, Nakamura T, Toba T, Kajiwara N, Kato H, Shimizu Y. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng 2004; 10: 771-779.
66. Sun CK, Lin YC, Yuen CM, Chua S, Chang LT, Sheu JJ, Lee FY, Fu M, Leu S, Yip HK. Enhanced protection against pulmonary hypertension with sildenafil and endothelial progenitor cell in rats. Int J Cardiol 2012; 162: 45-58.
67. Mirsky R, Jahn S, Koskenvuo JW, Sievers RE, Yim SM, Ritner C, Bernstein HS, Angeli FS, Boyle AJ, De Marco T, Yeghiazarians Y. Treatment of pulmonary arterial hypertension with circulating angiogenic cells. Am J Physiol Lung Cell Mol Physiol 2011; 301:L12-L19.
68. Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, Zhu JH, Chen JZ. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007; 49: 1566-1571.
69. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM. Cxc chemokines in angiogenesis. J Leukoc Biol 2000; 68: 1-8.
70. Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EGE, Walenkamp AME: A review on CXCR4/ CXCL12 axis in oncology: no place to hide. Eur J Cancer 2013; 49: 219-230.
71. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362: 697-703.
72. Yu L, Hales C. Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Respir Res 2011; 12: 21.
73. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106: 1311-1319.
74. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, Voelkel NF, Tuder RM. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001; 15: 427-438.
75. Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 2000; 50: 472-479.
76. Christou H, Yoshida A, Arthur V, Morita T, Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 1998; 18: 768-776.
77. Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 1995; 95: 1798-1807.
78. Arcot SS, Lipke DW, Gillespie MN, Olson JW. Alterations of growth factor transcripts in rat lungs during development of monocrotalineinduced pulmonary hypertension. Biochem Pharmacol 1993; 46: 1086-1091.
79. Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M, Sasano H, Kondo T, Nukiwa T. Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004; 169: 1203-1208.
80. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS. Pigment epitheliumderived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004; 170: 242-251.
81. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001; 163: 737-744.
82. Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, Lemarchand P, Eddahibi S. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2000; 23: 762-771.
83. Zhao YD, Courtman DW, Ng DS, Robb MJ, Deng YP, Trogadis J, Han RN, Stewart DJ. Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am J Respir Cell Mol Biol 2006; 35: 182-189.
84. Farkas L, Farkas D, Ask K, Moller A, Gauldie J, Margetts P, Inman M, Kolb M. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 2009; 119: 1298-1311.
85. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-526.
86. 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.
87. Villanueva MET, Zaher FM, Svinarich DM, Konduri GG. Decreased gene expression of endothelial nitric oxide synthase in newborns with persistent pulmonary hypertension. Pediatr Res 1998; 44: 338-343.
88. Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 1642-1644.
89. Le Cras TD, Xue C, Rengasamy A, Johns RA. Chronic hypoxia upregulates endothelial and inducible no synthase gene and protein expression in rat lung. Am J Physiol 1996; 270:L164-L170.
90. Mason NA, Springall DR, Burke M, Pollock J, Mikhail G, Yacoub MH, Polak JM. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 1998; 185: 313-318.
91. Champion HC, Bivalacqua TJ, Greenberg SS, Giles TD, Hyman AL, Kadowitz PJ. Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. Proc Natl Acad Sci USA 2002; 99: 13248-13253.
92. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. 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 2005; 96: 442-450.
93. Zhu JH, Wang XX, Zhang FR, Shang YP, Tao QM, Zhu JH, Chen JZ. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transplantat 2008; 12: 650-655.
94. Zhao Y-Y, Zhao YD, Mirza MK, Huang JH, Potula H-HSK, Vogel SM, Brovkovych V, Yuan JXJ, Wharton J, Malik AB. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 2009; 119: 2009-2018.
95. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999; 159: 1925-1932.
96. Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, Alger LA, Tuder RM, Voelkel NF. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999; 103: 1509-1515.
97. Nagaya N, Yokoyama C, Kyotani S, Shimonishi M, Morishita R, Uematsu M, Nishikimi T, Nakanishi N, Ogihara T, Yamagishi M, Miyatake K, Kaneda Y, Tanabe T. Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats. Circulation 2000; 102: 2005-2010.
98. Suhara H, Sawa Y, Fukushima N, Kagisaki K, Yokoyama C, Tanabe T, Ohtake S, Matsuda H. Gene transfer of human prostacyclin synthase into the liver is effective for the treatment of pulmonary hypertension in rats. J Thorac Cardiovasc Surg 2002; 123: 855-861.
99. Tahara N, Kai H, Niiyama H, Mori T, Sugi Y, Takayama N, Yasukawa H, Numaguchi Y, Matsui H, Okumura K, Imaizumi T. Repeated gene transfer of naked prostacyclin synthase plasmid into skeletal muscles attenuates monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Hum Gene Ther 2004; 15: 1270-1278.
100. Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymal stem cellbased prostacyclin synthase gene therapy for pulmonary hypertension rats. Basic Res Cardiol 2010; 105: 409-417.
101. Partanen J, Armstrong E, Makela TP, Korhonen J, Sandberg M, Renkonen R, Knuutila S, Huebner K, Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 1992; 12: 1698-1707.
102. Iwama A, Hamaguchi I, Hashiyama M, Murayama Y, Yasunaga K, Suda T. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem Biophys Res Commun 1993; 195: 301-309.
103. Sato TN, Qin Y, Kozak CA, Audus KL. Tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci USA 1993; 90: 9355-9358.
104. Schnurch H, Risau W. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 1993; 119: 957-968.
105. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretiontrap expression cloning. Cell 1996; 87: 1161-1169.
106. Stratmann A, Risau W, Plate KH. Cell typespecific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 1998; 153: 1459-1466.
107. Sugimachi K, Tanaka S, Taguchi K, Aishima S, Shimada M, Tsuneyoshi M. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J Clin Pathol 2003; 56: 854-860.
108. Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U. Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 2004; 24: 1803-1809.
109. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006; 27: 552-558.
110. Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999; 274: 15732-15739.
111. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 2002; 99: 11205-11210.
112. 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.
113. Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL, Jamieson SW, Thistlethwaite PA. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 2003; 100: 12331-12336.
114. Reynolds AM, Xia W, Holmes MD, Hodge SJ, Danilov S, Curiel DT, Morrell NW, Reynolds PN. Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 292:L1182-L1192.
115. Reynolds AM, Holmes MD, Danilov SM, Reynolds PN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 2012; 39: 329-343.
116. Yang J, Davies RJ, Southwood M, Long L, Yang X, Sobolewski A, Upton PD, Trembath RC, Morrell NW. Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension. Circ Res 2008; 102: 1212-1221.