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Molecular mechanisms of endothelial hyperpermeability: implications in inflammation

  • Puneet Kumar (a1), Qiang Shen (a1), Christopher D. Pivetti (a1), Eugene S. Lee (a1), Mack H. Wu (a1) and Sarah Y. Yuan (a1)...

Endothelial hyperpermeability is a significant problem in vascular inflammation associated with trauma, ischaemia–reperfusion injury, sepsis, adult respiratory distress syndrome, diabetes, thrombosis and cancer. An important mechanism underlying this process is increased paracellular leakage of plasma fluid and protein. Inflammatory stimuli such as histamine, thrombin, vascular endothelial growth factor and activated neutrophils can cause dissociation of cell–cell junctions between endothelial cells as well as cytoskeleton contraction, leading to a widened intercellular space that facilitates transendothelial flux. Such structural changes initiate with agonist–receptor binding, followed by activation of intracellular signalling molecules including calcium, protein kinase C, tyrosine kinases, myosin light chain kinase, and small Rho-GTPases; these kinases and GTPases then phosphorylate or alter the conformation of different subcellular components that control cell–cell adhesion, resulting in paracellular hypermeability. Targeting key signalling molecules that mediate endothelial-junction–cytoskeleton dissociation demonstrates a therapeutic potential to improve vascular barrier function during inflammatory injury.

Corresponding author
*Corresponding author: Sarah Yuan, Department of Surgery, University of California Davis Medical Center, 4625 2nd Avenue, Room 3006, Sacramento, CA 95817, USA. Tel: +1 916 703 0422; Fax: +1 916 703 0421; E-mail:
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1Bauer P.M. et al. (2005) Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 102, 204-209
2Gratton J.P., Bernatchez P. and Sessa W.C. (2004) Caveolae and caveolins in the cardiovascular system. Circulation Research 94, 1408-1417
3Lin M.I. et al. (2007) Caveolin-1-deficient mice have increased tumor microvascular permeability, angiogenesis, and growth. Cancer Research 67, 2849-2856
4Razani B. et al. (2001) Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. Journal of Biological Chemistry 276, 38121-38138
5Mehta D. and Malik A.B. (2006) Signaling mechanisms regulating endothelial permeability. Physiological Reviews 86, 279-367
6Dvorak A.M. et al. (1996) The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. Journal of Leukocyte Biology 59, 100-115
7Curry F.E. and Adamson R.H. (1999) Transendothelial pathways in venular microvessels exposed to agents which increase permeability: the gaps in our knowledge. Microcirculation 6, 3-5
8Dvorak A.M. (2005) Mast cell-derived mediators of enhanced microvascular permeability, vascular permeability factor/vascular endothelial growth factor, histamine, and serotonin, cause leakage of macromolecules through a new endothelial cell permeability organelle, the vesiculo-vacuolar organelle. Chemical Immunology and Allergy 85, 185-204
9Iyer S. et al. (2004) VE-cadherin-p120 interaction is required for maintenance of endothelial barrier function. American Journal of Physiology – Lung Cellular and Molecular Physiology 286, L1143-1153
10Xiao K. et al. (2005) p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin. Molecular Biology of the Cell 16, 5141-5151
11Esser S. et al. (1998) Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. Journal of Cell Science 111, 1853-1865
12Dejana E. (2004) Endothelial cell-cell junctions: happy together. Nature Reviews Molecular Cell Biology 5, 261-270
13Tiruppathi C. et al. (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation 13, 693-708
14Yuan S.Y. (2002) Protein kinase signaling in the modulation of microvascular permeability. Vascular Pharmacology 39, 213-223
15Yuan S.Y. et al. (2007) Microvascular permeability in diabetes and insulin resistance. Microcirculation 14, 363-373
16Isshiki M. et al. (1998) Endothelial Ca2+ waves preferentially originate at specific loci in caveolin-rich cell edges. Proceedings of the National Academy of Sciences of the United States of America 95, 5009-5014
17Maekawa M. et al. (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285, 895-898
18Mehta D., Rahman A. and Malik A.B. (2001) Protein kinase C-alpha signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. Journal of Biological Chemistry 276, 22614-22620
19Verin A.D. et al. (2000) Role of ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction. American Journal of Physiology – Lung Cellular and Molecular Physiology 279, L360-370
20Stasek J.E. Jr, Patterson C.E. and Garcia J.G. (1992) Protein kinase C phosphorylates caldesmon77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial cell monolayers. Journal of Cellular Physiology 153, 62-75
21Sandoval R. et al. (2001) Ca(2+) signalling and PKCalpha activate increased endothelial permeability by disassembly of VE-cadherin junctions. Journal of Physiology 533, 433-445
22Clarke H., Soler A.P. and Mullin J.M. (2000) Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheets. Journal of Cell Science 113 (Pt 18), 3187-3196
23Aramoto H. et al. (2004) Vascular endothelial growth factor stimulates differential signaling pathways in in vivo microcirculation. American Journal of Physiology – Heart and Circulatory Physiology 287, H1590-1598
24Bates D.O. and Curry F.E. (1997) Vascular endothelial growth factor increases microvascular permeability via a Ca(2+)-dependent pathway. American Journal of Physiology 273, H687-694
25Breslin J.W. et al. (2003) VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. American Journal of Physiology – Heart and Circulatory Physiology 284, H92-H100
26Lal B.K. et al. (2001) VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways. Microvascular Research 62, 252-262
27Varma S. et al. (2002) p42/44MAPK regulates baseline permeability and cGMP-induced hyperpermeability in endothelial cells. Microvascular Research 63, 172-178
28Wu H.M. et al. (1999) Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability. American Journal of Physiology 276, H535-542
29Stockton R.A., Schaefer E. and Schwartz M.A. (2004) p21-activated kinase regulates endothelial permeability through modulation of contractility. Journal of Biological Chemistry 279, 46621-46630
30Wu M.H. et al. (2003) Focal adhesion kinase mediates porcine venular hyperpermeability elicited by vascular endothelial growth factor. Journal of Physiology 552, 691-699
31Gavard J. and Gutkind J.S. (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nature Cell Biology 8, 1223-1234
32Eliceiri B.P. et al. (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Molecular Cell 4, 915-924
33Birukov K.G. et al. (2001) Differential regulation of alternatively spliced endothelial cell myosin light chain kinase isoforms by p60(Src). Journal of Biological Chemistry 276, 8567-8573
34Wu M.H., Ustinova E. and Granger H.J. (2001) Integrin binding to fibronectin and vitronectin maintains the barrier function of isolated porcine coronary venules. Journal of Physiology 532, 785-791
35Shajahan A.N. et al. (2004) Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells. Journal of Biological Chemistry 279, 20392-20400
36Miao H. et al. (2002) Differential regulation of Rho GTPases by beta1 and beta3 integrins: the role of an extracellular domain of integrin in intracellular signaling. Journal of Cell Science 115, 2199-2206
37Mammoto A., Mammoto T. and Ingber D.E. (2008) Rho signaling and mechanical control of vascular development. Current Opinion in Hematology 15, 228-234
38Breslin J.W. et al. (2006) Involvement of ROCK-mediated endothelial tension development in neutrophil-stimulated microvascular leakage. American Journal of Physiology – Heart and Circulatory Physiology 290, H741-750
39Breslin J.W. and Yuan S.Y. (2004) Involvement of RhoA and Rho kinase in neutrophil-stimulated endothelial hyperpermeability. American Journal of Physiology – Heart and Circulatory Physiology 286, H1057-1062
40Sun H. et al. (2006) Rho and ROCK signaling in VEGF-induced microvascular endothelial hyperpermeability. Microcirculation 13, 237-247
41van Nieuw Amerongen G.P. et al. (2000) Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circulation Research 87, 335-340
42Patil S.B. and Bitar K.N. (2006) RhoA- and PKC-alpha-mediated phosphorylation of MYPT and its association with HSP27 in colonic smooth muscle cells. American Journal of Physiology – Gastrointestinal and Liver Physiology 290, G83-95
43Garcia J.G. et al. (2001) Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. Journal of Clinical Investigation 108, 689-701
44Liu F. et al. (2002) Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3beta. FASEB Journal 16, 950-962
45Kouklis P. et al. (2004) Cdc42 regulates the restoration of endothelial barrier function. Circulation Research 94, 159-166
46Moore T.M. et al. (1998) Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP. American Journal of Physiology 275, L203-222
47Lampugnani M.G. et al. (1991) The role of integrins in the maintenance of endothelial monolayer integrity. Journal of Cell Biology 112, 479-490
48Hill S.J. et al. (1997) International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacological Reviews 49, 253-278
49Parsons M.E. and Ganellin C.R. (2006) Histamine and its receptors. British Journal of Pharmacology 147 Suppl 1, S127-135
50Clough G.F., Bennett A.R. and Church M.K. (1998) Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging. British Journal of Dermatology 138, 806-814
51Yuan S.Y. (2000) Signal transduction pathways in enhanced microvascular permeability. Microcirculation 7, 395-403
52Wu M.H., Yuan S.Y. and Granger H.J. (2005) The protein kinase MEK1/2 mediate vascular endothelial growth factor- and histamine-induced hyperpermeability in porcine coronary venules. Journal of Physiology 563, 95-104
53Guo M. et al. (2008) VE-cadherin and beta-catenin binding dynamics during histamine-induced endothelial hyperpermeability. American Journal of Physiology - Cell Physiology 294, C977-984
54Shasby D.M. et al. (2002) Histamine stimulates phosphorylation of adherens junction proteins and alters their link to vimentin. American Journal of Physiology – Lung Cellular and Molecular Physiology 282, L1330-1338
55Bogatcheva N.V., Garcia J.G. and Verin A.D. (2002) Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry 67, 75-84
56Borbiev T. et al. (2003) Role of CaM kinase II and ERK activation in thrombin-induced endothelial cell barrier dysfunction. American Journal of Physiology – Lung Cellular and Molecular Physiology 285, L43-54
57Birukova A.A. et al. (2004) Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB Journal 18, 1879-1890
58Holinstat M. et al. (2003) Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. Journal of Biological Chemistry 278, 28793-28798
59Grand R.J., Turnell A.S. and Grabham P.W. (1996) Cellular consequences of thrombin-receptor activation. The Biochemical Journal 313, 353-368
60Senger D.R. et al. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983-985
61Weis S.M. and Cheresh D.A. (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497-504
62Takahashi H. et al. (2004) A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1. Journal of Biological Chemistry 279, 46304-46314
63Zachary I. (2003) VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochemical Society Transactions 31, 1171-1177
64Behzadian M.A. et al. (2003) VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. FASEB Journal 17, 752-754
65Kelly M., Hwang J.M. and Kubes P. (2007) Modulating leukocyte recruitment in inflammation. Journal of Allergy and Clinical Immunology 120, 3-10
66Kubes P. (2002) The complexities of leukocyte recruitment. Seminars in Immunology 14, 65-72
67Liu Y. et al. (2004) Regulation of leukocyte transmigration: cell surface interactions and signaling events. Journal of Immunology 172, 7-13
68Rao R.M. et al. (2005) Emerging topics in the regulation of leukocyte transendothelial migration. Microcirculation 12, 83-89
69Rao R.M. et al. (2007) Endothelial-dependent mechanisms of leukocyte recruitment to the vascular wall. Circulation Research 101, 234-247
70Rosenkranz A.R. and Mayadas T.N. (1999) Leukocyte-endothelial cell interactions - lessons from knockout mice. Experimental Nephrology 7, 125-136
71Zarbock A. and Ley K. (2008) Mechanisms and consequences of neutrophil interaction with the endothelium. American Journal of Pathology 172, 1-7
72Sarelius I.H. et al. (2006) Macromolecule permeability of in situ and excised rodent skeletal muscle arterioles and venules. American Journal of Physiology – Heart and Circulatory Physiology 290, H474-480
73Yuan S.Y. et al. (2002) Myosin light chain phosphorylation in neutrophil-stimulated coronary microvascular leakage. Circulation Research 90, 1214-1221
74Tinsley J.H. et al. (2002) Src-dependent, neutrophil-mediated vascular hyperpermeability and beta-catenin modification. American Journal of Physiology – Cell Physiology 283, C1745-1751
75Chiba Y. et al. (2001) Activation of rho is involved in the mechanism of hydrogen-peroxide-induced lung edema in isolated perfused rabbit lung. Microvascular Research 62, 164-171
76Sumagin R., Lomakina E. and Sarelius I.H. (2008) Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling. American Journal of Physiology – Heart and Circulatory Physiology 295, H969-H977
77Usatyuk P.V. et al. (2003) Role of Ca2+ in diperoxovanadate-induced cytoskeletal remodeling and endothelial cell barrier function. American Journal of Physiology – Lung Cellular and Molecular Physiology 285, L1006-1017
78Usatyuk P.V. et al. (2003) Redox regulation of reactive oxygen species-induced p38 MAP kinase activation and barrier dysfunction in lung microvascular endothelial cells. Antioxidants and Redox Signalling 5, 723-730
79Blackwell T.S. and Christman J.W. (1997) The role of nuclear factor-kappa B in cytokine gene regulation. American Journal of Respiratory Cell and Molecular Biology 17, 3-9
80Reutershan J. and Ley K. (2004) Bench-to-bedside review: acute respiratory distress syndrome - how neutrophils migrate into the lung. Critical Care 8, 453-461
81Hu G. et al. (2008) Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability. Circulation Research 102, e120-131
82Bhatia M. and Moochhala S. (2004) Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. Journal of Pathology 202, 145-156
83Groeneveld A.B. (2002) Vascular pharmacology of acute lung injury and acute respiratory distress syndrome. Vascular Pharmacology 39, 247-256
84Hinshaw L.B., Jordan M.M. and Vick J.A. (1961) Histamine release and endotoxin shock in the primate. Journal of Clinical Investigation 40, 1631-1637
85Nagy S. (1990) The role of histamine release in shock. Acta Physiologica Hungarica 76, 3-12
86Breil I. et al. (1997) Effects of bradykinin, histamine and serotonin on pulmonary vascular resistance and permeability. Acta Physiologica Scandinavica 159, 189-198
87Bauer T.T. et al. (2000) Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls. Thorax 55, 46-52
88Hamacher J. et al. (2002) Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 166, 651-656
89Windsor A.C. et al. (1993) Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation. Journal of Clinical Investigation 91, 1459-1468
90Geiser T. et al. (2001) Pulmonary edema fluid from patients with acute lung injury augments in vitro alveolar epithelial repair by an IL-1beta-dependent mechanism. American Journal of Respiratory and Critical Care Medicine 163, 1384-1388
91Gilmont R.R. et al. (1998) Effects of glutathione depletion on oxidant-induced endothelial cell injury. Journal of Surgical Research 80, 62-68
92Wang Q. et al. (2007) Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS. Free Radical Biology and Medicine 43, 1048-1060
93Aktan A. and Yalcin A. (1998) Ischemia-reperfusion injury, reactive oxygen metabolites, and the Surgeon. Turkish Journal of Medical Sciences 28, 1-5
94Chua C.C., Hamdy R.C. and Chua B.H. (1998) Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Radical Biology and Medicine 25, 891-897
95Abumiya T. et al. (2005) Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats. Brain Research 1049, 95-103
96Godzich M. et al. (2006) Activation of the stress protein response prevents the development of pulmonary edema by inhibiting VEGF cell signaling in a model of lung ischemia-reperfusion injury in rats. FASEB Journal 20, 1519-1521
97Nosal'ova V. et al. (2008) Effect of H1 antihistamines in a model of mesenteric ischaemia/reperfusion. Inflammation Research 57 (Suppl 1), S55-56
98Collard C.D. et al. (1999) Complement activation following oxidative stress. Molecular Immunology 36, 941-948
99Carden D.L. and Granger D.N. (2000) Pathophysiology of ischaemia-reperfusion injury. Journal of Pathology 190, 255-266
100Hirahashi J. et al. (2006) Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25, 271-283
101Alexander J.S. and Elrod J.W. (2002) Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. Journal of Anatomy 200, 561-574
102Chehade J.M., Haas M.J. and Mooradian A.D. (2002) Diabetes-related changes in rat cerebral occludin and zonula occludens-1 (ZO-1) expression. Neurochemical Research 27, 249-252
103Davidson M.K. et al. (2000) Reduced expression of the adherens junction protein cadherin-5 in a diabetic retina. American Journal of Ophthalmology 129, 267-269
104Lee A.Y. and Chung S.S. (1999) Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB Journal 13, 23-30
105Bonnardel-Phu E. et al. (1999) Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo. Diabetes 48, 2052-2058
106Otero K. et al. (2001) Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells. The Biochemical Journal 359, 567-574
107Schmidt A.M. et al. (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochimica et Biophysica Acta 1498, 99-111
108Yamagishi S. et al. (2002) Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. Journal of Biological Chemistry 277, 20309-20315
109Brownlee M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615-1625
110Harrington E.O. et al. (2003) Role of protein kinase C isoforms in rat epididymal microvascular endothelial barrier function. American Journal of Respiratory Cell and Molecular Biology 28, 626-636
111Tinsley J.H., Teasdale N.R. and Yuan S.Y. (2004) Involvement of PKCdelta and PKD in pulmonary microvascular endothelial cell hyperpermeability. American Journal of Physiology – Cell Physiology 286, C105-111
112Yuan S.Y. et al. (2000) Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circulation Research 87, 412-417
113Guo M. et al. (2003) Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiological Genomics 12, 139-146
114Caldwell R.B. et al. (2005) Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Current Drug Targets 6, 511-524
115Hashizume H. et al. (2000) Openings between defective endothelial cells explain tumor vessel leakiness. American Journal of Pathology 156, 1363-1380
116Morikawa S. et al. (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. American Journal of Pathology 160, 985-1000
117Piulats J. and Mitjans F. (2008) Angiogenesis switch pathways. In Principles of Molecular Oncology (3rd edn) (Bronchud, M.H. et al.), pp. 239-256, Humana Press, Totowa, NJ, USA
118Anan K. et al. (1996) Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119, 333-339
119Dvorak H.F. et al. (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. American Journal of Pathology 146, 1029-1039
120Lee F.Y. et al. (2008) Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models. Clinical Cancer Research 14, 8123-8131
121Yuan F. et al. (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proceedings of the National Academy of Sciences of the United States of America 93, 14765-14770
122Wu M.H. (2005) Endothelial focal adhesions and barrier function. Journal of Physiology 569, 359-366
123Kargozaran H. et al. (2007) A role for endothelial-derived matrix metalloproteinase-2 in breast cancer cell transmigration across the endothelial-basement membrane barrier. Clinical and Experimental Metastasis 24, 495-502
124Brigham K.L., Bowers R.E. and Owen P.J. (1976) Effects of antihistamines on the lung vascular response to histamine in unanesthetized sheep. Diphenhydramine prevention of pulmonary edema and increased permeability. Journal of Clinical Investigation 58, 391-398
125Cordeiro P.G. et al. (2000) Prevention of ischemia-reperfusion injury in a rat skin flap model: the role of mast cells, cromolyn sodium, and histamine receptor blockade. Plastic and Reconstructive Surgery 105, 654-659
126Elenkov I.J. (2004) Glucocorticoids and the Th1/Th2 balance. Annals of the New York Academy of Sciences 1024, 138-146
127Svedmyr N. (1982) Effects of glucocorticoids on the airways. European Journal of Respiratory Diseases (Suppl) 122, 48-53
128Gerber H.P. et al. (2000) Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Research 60, 6253-6258
129Zhang J. et al. (2007) Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 109, 1478-1486
130Aiello L.P. et al. (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proceedings of the National Academy of Sciences of the United States of America 92, 10457-10461
131Robinson G.S. et al. (2001) Nonvascular role for VEGF: VEGFR-1, 2 activity is critical for neural retinal development. FASEB Journal 15, 1215-1217
132Haritoglou C. et al. (2006) Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 26, 999-1005
133Whittles C.E. et al. (2002) ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity. Microcirculation 9, 513-522
134van Nieuw Amerongen G.P. and van Hinsbergh V.W. (2002) Targets for pharmacological intervention of endothelial hyperpermeability and barrier function. Vascular Pharmacology 39, 257-272
135Gavard J., Patel V. and Gutkind J.S. (2008) Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Developmental Cell 14, 25-36
136Scheppke L. et al. (2008) Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. Journal of Clinical Investigation 118, 2337-2346
137Dhainaut J.F., Yan S.B. and Claessens Y.E. (2004) Protein C/activated protein C pathway: overview of clinical trial results in severe sepsis. Critical Care Medicine 32, S194-201
138Riewald M. et al. (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296, 1880-1882
139Bae J.S. et al. (2007) The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110, 3909-3916
140Feistritzer C. and Riewald M. (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105, 3178-3184
141Kurosawa S., Esmon C.T. and Stearns-Kurosawa D.J. (2000) The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. Journal of Immunology 165, 4697-4703
142Franscini N. et al. (2004) Gene expression profiling of inflamed human endothelial cells and influence of activated protein C. Circulation 110, 2903-2909
143Joyce D.E. et al. (2001) Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. Journal of Biological Chemistry 276, 11199-11203
144Wong S.S. et al. (2004) Drotrecogin alfa (activated) prevents smoke-induced increases in pulmonary microvascular permeability and proinflammatory cytokine IL-1beta in rats. Lung 182, 319-330
145Teke Z. et al. (2008) Activated protein C attenuates intestinal reperfusion-induced acute lung injury: an experimental study in a rat model. American Journal of Surgery 195, 861-873
146Aiello L.P. et al. (1997) Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 46, 1473-1480
147Ishii H. et al. (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272, 728-731
148Koksel O. et al. (2005) Rho-kinase (ROCK-1 and ROCK-2) upregulation in oleic acid-induced lung injury and its restoration by Y-27632. European Journal of Pharmacology 510, 135-142
149Olson M.F. (2008) Applications for ROCK kinase inhibition. Current Opinion in Cell Biology 20, 242-248
150Yin L. et al. (2007) Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Molecular Cancer Therapeutics 6, 1517-1525
151Arita R. et al. (2009) Rho kinase inhibition by fasudil ameliorates diabetes-induced microvascular damage. Diabetes 58, 215-226
152Peng F. et al. (2008) RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes 57, 1683-1692
153van Nieuw Amerongen G.P. et al. (2000) Simvastatin improves disturbed endothelial barrier function. Circulation 102, 2803-2809
154Zeng L. et al. (2005) HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation. FASEB Journal 19, 1845-1847
Mammoto A. et al. (2008) Rho signaling and mechanical control of vascular development. Vascular Biology 15, 228-234
van Nieuw Amerongen G.P. et al. (2003) Targets for pharmacological intervention of endothelial hyperpermeability and barrier function. Vascular Pharmacology 39, 257-272
Groeneveld A.B. et al. (2003) Vascular pharmacology of acute lung injury and acute respiratory distress syndrome. Vascular Pharmacology 39, 247-256
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