The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury

Expert Opinion on Therapeutic Targets

Volumn 13, Issue 1, 2009, Pages 39-53

  Van Der Heijden, Melanie ^a   Van Nieuw Amerongen, Geerten P ^a   Chedamni, Sunita ^a   Van Hinsbergh, Victor W M ^a   Groeneveld, A B Johan ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Acute lung injury; Acute respiratory distress syndrome; Angiopoietin; Critical care; Inflammation; Intensive care unit; Leakage; Permeability; Sepsis; Tie1; Tie2

Indexed keywords

ANGIOPOIETIN; ANGIOPOIETIN 1; ANGIOPOIETIN RECEPTOR; ANGIOTENSIN I; ANGIOTENSIN II; C REACTIVE PROTEIN; ENDOTHELIAL NITRIC OXIDE SYNTHASE; INTERLEUKIN 6; PROCALCITONIN; RECOMBINANT PROTEIN; TIE 1 RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ACUTE LUNG INJURY; ADULT RESPIRATORY DISTRESS SYNDROME; APOPTOSIS; BLOOD PRESSURE; BLOOD VESSEL PERMEABILITY; CELL ADHESION; CELL MIGRATION; CRITICALLY ILL PATIENT; ENDOTHELIUM; ENDOTOXEMIA; ENZYME ACTIVITY; EXPERIMENTAL MODEL; GENE EXPRESSION; HEART OUTPUT; HOMEOSTASIS; HUMAN; INFLAMMATION; LUNG EDEMA; LUNG INJURY; LUNG VASOCONSTRICTION; LYMPHATIC SYSTEM DISEASE; MESENTERIC ARTERY; NONHUMAN; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PULMONARY HYPERTENSION; REVIEW; SEPSIS; SHOCK; SIDE EFFECT; SKIN BLOOD VESSEL; STIMULUS RESPONSE; TREATMENT OUTCOME; VASCULARIZATION; DRUG ANTAGONISM; DRUG EFFECT; PHYSIOLOGY;

ACUTE LUNG INJURY; ANGIOPOIETINS; HUMANS; RECEPTOR, TIE-2; SEPSIS;

EID: 61449428503     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728220802626256     Document Type: Review

References (115)

1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709 (Pubitemid 32204987)
2. Wind J, Versteegt J, Twisk J, et al. Epidemiology of acute lung injury and acute respiratory distress syndrome in The Netherlands: a survey. Respir Med 2007;101:2091-2098 (Pubitemid 47324255)
3. Van Gestel A, Bakker J, Veraart CP, et al. Prevalence and incidence of severe sepsis in Dutch intensive care units. Crit Care 2004;8:R153-62
4. Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008;178:618-623
5. 67gallium pulmonary leak index in assessing the severity and course of the adult respiratory distress syndrome. Crit Care Med 1996;24:1467-1472 (Pubitemid 26313746)
6. Groeneveld AB. Vascular pharmacology of acute lung injury and acute respiratory distress syndrome. Vascul Pharmacol 2002;39:247-256 (Pubitemid 37490750)
7. Hudson LD, Milberg JA, Anardi D, et al. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:293-301
8. Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005;128:525-532 (Pubitemid 41140476)
9. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008;295:L379-99
10. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-150 (Pubitemid 36056721)
11. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006;86:279-367 • The authors present an extensive review of the signalling mechanisms involved in the regulation of both the endothelial transcellular and paracellular pathways of passage with excellent schematic overviews.
12. Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 2001;91:1487-1500 (Pubitemid 32900340)
13. Keller TT, Mairuhu AT, de Kruijf MD, et al. Infections and endothelial cells. Cardiovasc Res 2003;60:40-48 (Pubitemid 38373474)
14. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003;101:3765-3777 (Pubitemid 36857845)
15. Maniatis NA, Orfanos SE. The endothelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 2008;14:22-30
16. Witzenbichler B, Westermann D, Knueppel S, et al. Protective role of angiopoietin-1 in endotoxic shock. Circulation 2005;111:97-105 (Pubitemid 40070850)
17. Gallagher DC, Bhatt RS, Parikh SM, et al. Angiopoietin 2 is a potential mediator of high-dose interleukin 2-induced vascular leak. Clin Cancer Res 2007;13:2115-2120 (Pubitemid 46649880)
18. Bhandari V, Choo-Wing R, Lee CG, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 2006;12:1286-1293 • By using mice genetically deficient in Ang-2 and siRNA against Ang-2 in vivo, the authors are the first, to our knowledge, to demonstrate that Ang-2 has a crucial role in the pathogenesis of lung injury in vivo. (Pubitemid 44706931)
19. Siner JM, Bhandari V, Engle KM, et al. Elevated serum angiopoietin-2 levels are associated with increased mortality in sepsis. Shock 2008; in press, published online 11 September 2008, doi: 10.1097/ SHK.0b013e318188bd06
20. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 2008;29:656-661 (Pubitemid 351769925)
21. Ganter MT, Cohen MJ, Brohi K, et al. Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg 2008;247:320-326
22. Giuliano JS Jr, Lahni PM, Harmon K, et al. Admission angiopoietin levels in children with septic shock. Shock 2007;28:650-654 (Pubitemid 350135468)
23. Orfanos SE, Kotanidou A, Glynos C, et al. Angiopoietin-2 is increased in severe sepsis: Correlation with inflammatory mediators. Crit Care Med 2006;35:199-206
24. Parikh SM, Mammoto T, Schultz A, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 2006;3:356-370 •• The article presents patient and experimental in vivo and in vitro data on the role of Ang-2 in pulmonary vascular leakage. The authors were the first, to our knowledge, to describe the levels of Ang-2 in patients with sepsis and the association between this level and impaired oxygenation.
25. Mammoto T, Parikh SM, Mammoto A, et al. Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. J Biol Chem 2007;282:23910-23918 (Pubitemid 47328051)
26. Van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, et al. Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax 2008;63:903-909 • The authors were the first, to our knowledge, to report that the levels of Ang-2 in critically ill septic and non-septic patients are related to directly measured pulmonary permeability oedema.
27. Novotny NM, Lahm T, Markel TA, et al. Angiopoietin-1 in the treatment of ischemia and sepsis. Shock 2008; published online 11 September 2008, doi:0.1097/ SHK.0b013e3181862c63 28.
28. Kim SR, Lee KS, Park SJ, et al. Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury. Exp Mol Med 2008;40:320-31
29. McCarter SD, Lai PF, Suen RS, et al. Regulation of endothelin-1 by angiopoietin-1: implications for inflammation. Exp Biol Med (Maywood) 2006;231:985-991 (Pubitemid 43845564)
30. Xu J, Qu J, Cao L, et al. Mesenchymal stem cell-based angiopoietin-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J Pathol 2008;214:472-481 (Pubitemid 351340567)
31. McCarter SD, Mei SH, Lai PF, et al. Cell-based angiopoietin-1 gene therapy for acute lung injury. Am J Respir Crit Care Med 2007;175:1014-1026 (Pubitemid 46741753)
32. Mei SH, McCarter SD, Deng Y, et al. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007;4:1525-1537 (Pubitemid 47503045)
33. Childs EW, Tharakan B, Byrge N, et al. Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock. Am J Physiol Heart Circ Physiol 2008;294:H2285-95
34. Huang YQ, Sauthoff H, Herscovici P, et al. Angiopoietin-1 increases survival and reduces the development of lung edema induced by endotoxin administration in a murine model of acute lung injury. Crit Care Med 2008;36:262-267
35. Baffert F, Le T, Thurston G, et al. Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules. Am J Physiol Heart Circ Physiol 2006;290:H107-18
36. Gavard J, Patel V, Gutkind JS. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 2008;14:25-36
37. Thurston G, Suri C, Smith K, et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999;286:2511-2514 (Pubitemid 30026340)
38. Thurston G, Rudge JS, Ioffe E, et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000;6:460-463 (Pubitemid 30208166)
39. Roviezzo F, Tsigkos S, Kotanidou A, et al. Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther 2005;314:738-744
40. Lemieux C, Maliba R, Favier J, et al. Angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses. Blood 2005;105:1523-1530 (Pubitemid 40223669)
41. Wong MP, Chan SY, Fu KH, et al. The angiopoietins, tie2 and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non-small cell lung carcinomas. Lung Cancer 2000;29:11-22 (Pubitemid 30398555)
42. Sturn DH, Feistritzer C, Mosheimer BA, et al. Angiopoietin affects neutrophil migration. Microcirculation 2005;12:393-403 (Pubitemid 41122464)
43. Murdoch C, Tazzyman S, Webster S, et al. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol 2007;178:7405-7411 (Pubitemid 46847468)
44. Wong AL, Haroon ZA, Werner S, et al. Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ Res 1997;81:567-574 (Pubitemid 27432744)
45. Davis S, Papadopoulos N, Aldrich TH, et al. Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering. Nat Struct Biol 2003;10:38-44 (Pubitemid 36034175)
46. Eklund L, Olsen BR. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp Cell Res 2006;312:630-641 (Pubitemid 43290339)
47. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55-60 (Pubitemid 27450643)
48. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature 2000;407:242-248 •• The authors present a comprehensive review of the role of vascular endothelial growth factor, Ang-1 and Ang-2 during vessel formation and stabilisation.
49. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF- a and has a crucial role in the induction of inflammation. Nat Med 2006;12:235-239 •• The authors are the first, to our knowledge, to demonstrate that Ang-2 has a crucial role in inflammation in vivo by using mice genetically deficient in Ang-2. (Pubitemid 43214752)
50. Gamble JR, Drew J, Trezise L, et al. Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 2000;87:603-607 (Pubitemid 30745356)
51. Pizurki L, Zhou Z, Glynos K, et al. Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production. Br J Pharmacol 2003;139:329-336 (Pubitemid 36760365)
52. Li JJ, Huang YQ, Basch R, et al. Thrombin induces the release of angiopoietin-1 from platelets. Thromb Haemost 2001;85:204-206 (Pubitemid 32140561)
53. Fiedler U, Scharpfenecker M, Koidl S, et al. Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004;103:4150-4156 (Pubitemid 38685356)
54. Huang YQ, Li JJ, Hu L, et al. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood 2002;99:1646-1650
55. Mofarrahi M, Nouh T, Qureshi S, et al. Regulation of angiopoietin expression by bacterial lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol 2008;294:L955-63
56. Daly C, Pasnikowski E, Burova E, et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc Natl Acad Sci USA 2006;103:15491-15496 (Pubitemid 44625619)
57. Scharpfenecker M, Fiedler U, Reiss Y, et al. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 2005;118:771-780 (Pubitemid 40372585)
58. Harfouche R, Hussain SN. Signaling and regulation of endothelial cell survival by angiopoietin-2. Am J Physiol Heart Circ Physiol 2006;291:H1635-45 (Pubitemid 44497667)
59. Kim I, Kim JH, Moon SO, et al. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Oncogene 2000;19:4549-4552 (Pubitemid 30756901)
60. Karmpaliotis D, Kosmidou I, Ingenito EP, et al. Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2002;283:L585-95 (Pubitemid 34941007)
61. Abdulmalek K, Ashur F, Ezer N, et al. Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats. Am J Physiol Lung Cell Mol Physiol 2001;281:L582-90 (Pubitemid 32879210)
62. Daly C, Wong V, Burova E, et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 2004;18:1060-1071 (Pubitemid 38620245)
63. Tsigkos S, Zhou Z, Kotanidou A, et al. Regulation of Ang2 release by PTEN/PI3-kinase/Akt in lung microvascular endothelial cells. J Cell Physiol 2006;207:506-511
64. Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995;376:70-74
65. Saharinen P, Kerkela K, Ekman N, et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 2005;169:239-243 (Pubitemid 40656562)
66. Yuan HT, Venkatesha S, Chan B, et al. Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J 2007;21:3171-3183 (Pubitemid 47565536)
67. Marron MB, Singh H, Tahir TA, et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor tyrosine kinase Tie2. J Biol Chem 2007;282:30509-30517 • This article presents an intriguing mechanism by which Tie1 modulates ligand responsiveness of Tie2. (Pubitemid 350035225)
68. Van Hinsbergh VW, Koolwijk P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 2008;78:203-212 (Pubitemid 351556093)
69. Kim KL, Shin IS, Kim JM, et al. Interaction between Tie receptors modulates angiogenic activity of angiopoietin2 in endothelial progenitor cells. Cardiovasc Res 2006;72:394-402 (Pubitemid 44665844)
70. Fukuhara S, Sako K, Minami T, et al. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 2008;10:513-526 • This article explores how angiopoietin-Tie2 signalling plays distinct roles in both vascular quiescence and angiogenesis. (Pubitemid 351627371)
71. Saharinen P, Eklund L, Miettinen J, et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol 2008;10:527-537 • This article reports that cellular microenvironment-dependent receptor tyrosine kinase activation may explain how the angiopoietins play distinct roles in both angiogenesis and vessel stabilisation. (Pubitemid 351627372)
72. Xu Y, Yu Q. Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem 2001;276:34990-34998 (Pubitemid 37384504)
73. Marshall JC. Neutrophils in the pathogenesis of sepsis. Crit Care Med 2005;33:S502-5 (Pubitemid 41786001)
74. Abraham E. Neutrophils and acute lung injury. Crit Care Med 2003;31:S195-9 (Pubitemid 36458167)
75. Steeber DA, Tedder TF. Adhesion molecule cascades direct lymphocyte recirculation and leukocyte migration during inflammation. Immunol Res 2000;22:299-317 (Pubitemid 32382242)
76. Kim I, Moon SO, Park SK, et al. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ Res 2001;89:477-479
77. Hughes DP, Marron MB, Brindle NP. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-. B inhibitor ABIN-2. Circ Res 2003;92:630-636
78. Aplin AC, Gelati M, Fogel E, et al. Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis. Physiol Genomics 2006;27:20-28 (Pubitemid 44511822)
79. Kim I, Oh JL, Ryu YS, et al. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells. FASEB J 2002;16:126-128
80. Li X, Hahn CN, Parsons M, et al. Role of protein kinase C. in thrombin-induced endothelial permeability changes: inhibition by angiopoietin-1. Blood 2004;104:1716-1724 (Pubitemid 39202279)
81. Jho D, Mehta D, Ahmmed G, et al. Angiopoietin-1 opposes VEGF-induced increase in endothelial permeability by inhibiting TRPC1-dependent Ca 2+ influx. Circ Res 2005;96:1282-1290 (Pubitemid 40962106)
82. Ahmmed GU, Mehta D, Vogel S, et al. Protein kinase C a phosphorylates the TRPC1 channel and regulates store-operated Ca 2+ entry in endothelial cells. J Biol Chem 2004;279:20941-20949 (Pubitemid 38656493)
83. Mehta D, Ahmmed GU, Paria BC, et al. RhoA interaction with inositol 1,4,5-trisphosphate receptor and transient receptor potential channel-1 regulates Ca 2+ entry. Role in signaling increased endothelial permeability. J Biol Chem 2003;278:33492-33500
84. Van Hinsbergh VW, van Nieuw Amerongen GP. Intracellular signalling involved in modulating human endothelial barrier function. J Anat 2002;200:549-560 (Pubitemid 34823047)
85. Li X, Stankovic M, Bonder CS, et al. Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 2008;111:3489-3497
86. Wang Y, Pampou S, Fujikawa K, et al. Opposing effect of angiopoietin-1 on VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC β. J Cell Physiol 2004;198:53-61 (Pubitemid 38120966)
87. Van Nieuw Amerongen GP, Beckers CM, Achekar ID, et al. Involvement of Rho kinase in endothelial barrier maintenance. Arterioscler Thromb Vasc Biol 2007;27:2332-2339 (Pubitemid 350203947)
88. Peters S, Cree IA, Alexander R, et al. Angiopoietin modulation of vascular endothelial growth factor: effects on retinal endothelial cell permeability. Cytokine 2007;40:144-150 (Pubitemid 350180531)
89. Bannerman DD, Goldblum SE. Mechanisms of bacterial lipopolysaccharide- induced endothelial apoptosis. Am J Physiol Lung Cell Mol Physiol 2003;284:L899-914 (Pubitemid 36687124)
90. Gale NW, Thurston G, Hackett SF, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 2002;3:411-423
91. Liu XB, Jiang J, Gui C, et al. Angiopoietin-1 protects mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis through the PI3K/Akt pathway. Acta Pharmacol Sin 2008;29:815-822
92. Papapetropoulos A, Fulton D, Mahboubi K, et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 2000;275:9102-9105 (Pubitemid 30185122)
93. Kim I, Kim HG, So JN, et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ Res 2000;86:24-29 (Pubitemid 30044164)
94. Harfouche R, Hassessian HM, Guo Y, et al. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc Res 2002;64:135-147 (Pubitemid 34713240)
95. Tadros A, Hughes DP, Dunmore BJ, et al. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood 2003;102:4407-4409 (Pubitemid 37494102)
96. Van der Heijden M, Versteilen AM, Sipkema P, et al. Rho-kinase-dependent F-actin rearrangement is involved in the inhibition of PI3-kinase/Akt during ischemia-reperfusion-induced endothelial cell apoptosis. Apoptosis 2008;13:404-412
97. Kwak HJ, Lee SJ, Lee YH, et al. Angiopoietin-1 inhibits irradiation- and mannitol-induced apoptosis in endothelial cells. Circulation 2000;101:2317-2324 (Pubitemid 30317136)
98. Hall E, Brookes ZL. Angiopoietin-1 increases arteriolar vasoconstriction to phenylephrine during sepsis. Regul Pept 2005;131:34-37 (Pubitemid 41392989)
99. Sullivan CC, Du L, Chu D, et al. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 2003;100:12331-12336 (Pubitemid 37271560)
100. Suri C, McClain J, Thurston G, et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998;282:468-471 (Pubitemid 28483672)
101. Tammela T, Saaristo A, Lohela M, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 2005;105:4642-4648 (Pubitemid 40807283)
102. Long DA, Price KL, Ioffe E, et al. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int 2008;74:300-309 (Pubitemid 352001243)
103. Sarraf-Yazdi S, Mi J, Moeller BJ, et al. Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer. J Surg Res 2008;146:16-23
104. White RR, Shan S, Rusconi CP, et al. Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2. Proc Natl Acad Sci USA 2003;100:5028-5033 • The authors generated RNA aptamers that potently and selectively neutralised the interaction between Ang-2 and Tie2 and used them for suppression of angiogenesis in vivo. (Pubitemid 36542652)
105. Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 2004;6:507-516 • The authors generated antibodies and peptide-Fc fusion proteins that potently and selectively neutralised the interaction between Ang-2 and Tie2 and used them for suppression of angiogenesis and tumor growth in vivo. (Pubitemid 39469986)
106. Que-Gewirth NS, Sullenger BA. Gene therapy progress and prospects: RNA aptamers. Gene Ther 2007;14:283-291 • The authors present a comprehensive review on RNA aptamers and the progress of the use of aptamers in clinical settings. (Pubitemid 46231922)
107. Jeyaseelan S, Chu HW, Young SK, et al. Transcriptional profiling of lipopolysaccharide-induced acute lung injury. Infect Immun 2004;72:7247-7256 (Pubitemid 39552396)
108. Rojas M, Woods CR, Mora AL, et al. Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am J Physiol Lung Cell Mol Physiol 2005;288:L333-41 (Pubitemid 40105372)
109. Lin P, Buxton JA, Acheson A, et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci USA 1998;95:8829-8834 (Pubitemid 28350574)
110. Huegel R, Velasco P, De la Luz SM, et al. Novel anti-inflammatory properties of the angiogenesis inhibitor vasostatin. J Invest Dermatol 2007;127:65-74 (Pubitemid 46005662)
111. Calfee CS, Matthay MA. Nonventilatory treatments for acute lung injury and ARDS. Chest 2007;131:913-920 (Pubitemid 46446892)
112. Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 2007;100:174-190
113. Griffin JH, Fernandez JA, Gale AJ, et al. Activated protein C. J Thromb Haemost 2007;5 (Suppl 1): 73-80 (Pubitemid 46958820)
114. Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-1341 (Pubitemid 41362701)
115. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre Phase III randomised controled trial. Lancet 2007;369:836-843 (Pubitemid 46365900)