Venous endothelial injury in central nervous system diseases

BMC Medicine

Alireza Minagar⁴  Chaitanya Vijay Ganta³  Ikuo Tsunoda²  Leonard Prouty¹  Jonathan S Alexander³ 

[1] Department of Pathology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA;Department of Microbiology and Immunology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA;Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA;Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA

关键词: Inflammation;    ADEM;    CNS;    MS;    Venous;   

Others  :  855625
DOI  :  10.1186/1741-7015-11-219

 received in 2013-02-12, accepted in 2013-09-09,  发布年份 2013

【 摘 要 】

The role of the venous system in the pathogenesis of inflammatory neurological/neurodegenerative diseases remains largely unknown and underinvestigated. Aside from cerebral venous infarcts, thromboembolic events, and cerebrovascular bleeding, several inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and optic neuritis, appear to be associated with venous vascular dysfunction, and the neuropathologic hallmark of these diseases is a perivenous, rather than arterial, lesion. Such findings raise fundamental questions about the nature of these diseases, such as the reasons why their pathognomonic lesions do not develop around the arteries and what exactly are the roles of cerebral venous inflammation in their pathogenesis. Apart from this inflammatory-based view, a new hypothesis with more focus on the hemodynamic features of the cerebral and extracerebral venous system suggests that MS pathophysiology might be associated with the venous system that drains the CNS. Such a hypothesis, if proven correct, opens new therapeutic windows in MS and other neuroinflammatory diseases. Here, we present a comprehensive review of the pathophysiology of MS, ADEM, pseudotumor cerebri, and optic neuritis, with an emphasis on the roles of venous vascular system programming and dysfunction in their pathogenesis. We consider the fundamental differences between arterial and venous endothelium, their dissimilar responses to inflammation, and the potential theoretical contributions of venous insufficiency in the pathogenesis of neurovascular diseases.

【 授权许可】

   
2013 Alexander et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Schaller B: Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Brain Res Rev 2004, 46:243-260.
• [2]Haacke EM, Beggs CB, Habib C: The role of venous abnormalities in neurological disease. Rev Recent Clin Trials 2012, 7:100-116.
• [3]Bouvrée K, Brunet I, Del Toro R, Gordon E, Prahst C, Cristofaro B, Mathivet T, Xu Y, Soueid J, Fortuna V, Miura N, Aigrot MS, Maden CH, Ruhrberg C, Thomas JL, Eichmann A: Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation. Circ Res 2012, 111:437-445.
• [4]Compston A, Coles A: Multiple sclerosis. Lancet 2008, 372:1502-1517.
• [5]Alexander JS, Minagar A, Harper M, Robinson-Jackson S, Jennings M, Smith SJ: Proteomic analysis of human cerebral endothelial cells activated by multiple sclerosis serum and IFNbeta-1b. J Mol Neurosci 2007, 32:169-178.
• [6]Haghjooy Javanmard S, Saadatnia M, Homayouni V, Nikoogoftar M, Maghzi AH, Etemadifar M, Chaitanya VG, McGee JC, Minagar A, Alexander JS: Interferon-beta-1b protects against multiple sclerosis-induced endothelial cells apoptosis. Front Biosci (Elite Ed) 2012, 4:1368-1374.
• [7]Minagar A, Ostanin D, Long AC, Jennings M, Kelley RE, Sasaki M, Alexander JS: Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells. Mult Scler 2003, 9:235-238.
• [8]Ge Y, Law M, Herbert J, Grossman RI: Prominent perivenular spaces in multiple sclerosis as a sign of perivascular inflammation in primary demyelination. AJNR Am J Neuroradiol 2005, 26:2316-2319.
• [9]Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, Grossman RI: Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology 2004, 231:645-652.
• [10]Saindane AM, Law M, Ge Y, Johnson G, Babb JS, Grossman RI: Correlation of diffusion tensor and dynamic perfusion MR imaging metrics in normal-appearing corpus callosum: support for primary hypoperfusion in multiple sclerosis. AJNR Am J Neuroradiol 2007, 28:767-772.
• [11]Swank RL, Roth JG, Woody DC Jr: Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis. Neurol Res 1983, 5:37-59.
• [12]Simka M, Zaniewski M: Reinterpreting the magnetic resonance signs of hemodynamic impairment in the brains of multiple sclerosis patients from the perspective of a recent discovery of outflow block in the extracranial veins. J Neurosci Res 2010, 88:1841-1845.
• [13]Kalogeris TJ, Kevil CG, Laroux FS, Coe LL, Phifer TJ, Alexander JS: Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells. Am J Physiol 1999 , 276:L9-L19.
• [14]Amberger A, Maczek C, Jürgens G, Michaelis D, Schett G, Trieb K, Eberl T, Jindal S, Xu Q, Wick G: Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins. Cell Stress Chaperones 1997, 2:94-103.
• [15]Wang X, Feuerstein GZ: Induced expression of adhesion molecules following focal brain ischemia. J Neurotrauma 1995, 12:825-832.
• [16]Kevil CG, Payne DK, Mire E, Alexander JS: Vascular permeability factor/vascular endothelial cell growth factor-mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem 1998, 273:15099-15103.
• [17]Morita K, Sasaki H, Furuse M, Tsukita S: Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 1999, 147:185-194.
• [18]Burek M, Arias-Loza PA, Roewer N, Förster CY: Claudin-5 as a novel estrogen target in vascular endothelium. Arterioscler Thromb Vasc Biol 2010, 30:298-304.
• [19]Volgina NE, Gurina OI, Grinenko NF, Baklaushev VP, Ivanova NV, Chekhonin VP: Expression of tight junction proteins by umbilical vein epithelial cells co-cultured with allogenic astrocytes. Bull Exp Biol Med 2012, 154:124-129.
• [20]Chaitanya GV, Cromer WE, Wells SR, Jennings MH, Couraud PO, Romero IA, Weksler B, Erdreich-Epstein A, Mathis JM, Minagar A, Alexander JS: Gliovascular and cytokine interactions modulate brain endothelial barrier in vitro. J Neuroinflammation 2011, 162:1-16.
• [21]Adamson RH, Sarai RK, Altangerel A, Clark JF, Weinbaum S, Curry FE: Microvascular permeability to water is independent of shear stress, but dependent on flow direction. Am J Physiol Heart Circ Physiol 2013, 304:H1077-H1084.
• [22]Zakkar M, le Luong A, Chaudhury H, Ruud O, Punjabi PP, Anderson JR, Mullholand JW, Clements AT, Krams R, Foin N, Athanasiou T, Leen EL, Mason JC, Haskard DO, Evans PC: Dexamethasone arterializes venous endothelial cells by inducing mitogen-activated protein kinase phosphatase-1: a novel antiinflammatory treatment for vein grafts? Circulation 2011, 123:524-532.
• [23]Liu M, Kluger MS, D'Alessio A, García-Cardeña G, Pober JS: Regulation of arterial-venous differences in tumor necrosis factor responsiveness of endothelial cells by anatomic context. Am J Pathol 2008, 172:1088-1099.
• [24]Wu W, Xiao H, Laguna-Fernandez A, Villarreal G Jr, Wang KC, Geary GG, Zhang Y, Wang WC, Huang HD, Zhou J, Li YS, Chien S, Garcia-Cardena G, Shyy JY: Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a. Circulation 2011, 124:633-641.
• [25]Fang Y, Davies PF: Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Bio 2012, 32:979-987.
• [26]Kee HJ, Kwon JS, Shin S, Ahn Y, Jeong MH, Trichostatin KH: A prevents neointimal hyperplasia via activation of Krüppel like factor 4. Vascul Pharmacol 2011, 55:127-134.
• [27]SenBanerjee S, et al.: KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med 2004, 199:1305-1315.
• [28]Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK: Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem 2007, 282:13769-13779.
• [29]Schelling F: Damaging venous reflux into the skull or spine: relevance to multiple sclerosis. Med Hypotheses 1986, 21:141-148.
• [30]Lin Z, et al.: Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res 2005, 96:48-57.
• [31]Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA Jr, García-Cardeña G: Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 2006, 116:49-58.
• [32]Das H, Kumar A, Lin Z, Patino WD, Hwang PM, Feinberg MW, Majumder PK, Jain MK: Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci U S A 2006, 103:6653-6658.
• [33]Fledderus JO, van Thienen JV, Boon RA, Dekker RJ, Rohlena J, Volger OL, Bijnens AP, Daemen MJ, Kuiper J, van Berkel TJ, Pannekoek H, Horrevoets AJ: Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2. Blood 2007, 109:4249-4257.
• [34]van Agtmaal EL, Bierings R, Dragt BS, Leyen TA, Fernandez-Borja M, Horrevoets AJ, Voorberg J: The shear stress-induced transcription factor KLF2 affects dynamics and angiopoietin-2 content of Weibel-Palade bodies. PLoS One 2012, 7:e38399. 1–10
• [35]Methe H, Balcells M, Alegret Mdel C, Santacana M, Molins B, Hamik A, Jain MK, Edelman ER: Vascular bed origin dictates flow pattern regulation of endothelial adhesion molecule expression. Am J Physiol Heart Circ Physiol 2007, 292:H2167-H2175.
• [36]Sen-Banerjee S, Mir S, Lin Z, Hamik A, Atkins GB, Das H, Banerjee P, Kumar A, Jain MK: Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 2005, 112:720-726.
• [37]Ohnesorge N, Viemann D, Schmidt N, Czymai T, Spiering D, Schmolke M, Ludwig S, Roth J, Goebeler M, Schmidt M: Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4). J Biol Chem 2010, 285:26199-26210.
• [38]Ali F, Hamdulay SS, Kinderlerer AR, Boyle JJ, Lidington EA, Yamaguchi T, Soares MP, Haskard DO, Randi AM, Mason JC: Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1. J Thromb Haemost 2007, 5:2537-2546.
• [39]Franciotta D, Zardini E, Ravaglia S, Piccolo G, Andreoni L, Bergamaschi R, Romani A, Tavazzi E, Naldi P, Ceroni M, Marchioni E: Cytokines and chemokines in cerebrospinal fluid and serum of adult patients with acute disseminated encephalomyelitis. J Neurol Sci 2006, 247:202-207.
• [40]Huddleson JP, Ahmad N, Srinivasan S, Lingrel JB: Induction of KLF2 by fluid shear stress requires a novel promoter element activated by a phosphatidylinositol 3-kinase-dependent chromatin-remodeling pathway. J Biol Chem 2005 Jun 17, 280:23371-23379.
• [41]Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A: Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult Scler 2010, 16:801-809.
• [42]Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR: Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest 2012, 122:2454-2468.
• [43]Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ: Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol 2008, 65:199-204.
• [44]Sharp CD, Houghton J, Elrod JW, Warren A, Jackson TH 4th, Jawahar A, Nanda A, Minagar A, Alexander JS: N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am J Physiol Heart Circ Physiol 2005, 288:H1893-H1899.
• [45]Anand P, Shenoy R, Palmer JE, Baines AJ, Lai RY, Robertson J, Bird N, Ostenfeld T, Chizh BA: Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur J Pain 2011, 15:1040-1048.
• [46]Sansilvestri-Morel P, Rupin A, Badier-Commander C, Fabiani JN, Verbeuren TJ: Chronic venous insufficiency: dysregulation of collagen synthesis. Angiology 2003, 54:S13-S18.
• [47]McCollum PT, Bush JA, James G, et al.: Randomized phase II clinical trial of Avotermin versus placebo for scar improvement. Br J Surg 2011, 98:925-934.
• [48]McTaggart RA, Fischbein NJ, Elkins CJ, Hsiao A, Cutalo MJ, Rosenberg J, Dake MD, Zaharchuk G: Extracranial venous drainage patterns in patients with multiple sclerosis and healthy controls. AJNR Am J Neuroradiol 2012, 33:1615-1620.
• [49]Radak D, Kolar J, Tanaskovic S, Sagic D, Antonic Z, Mitrasinovic A, Babic S, Nenezic D, Ilijevski N: Morphological and haemodynamic abnormalities in the jugular veins of patients with multiple sclerosis. Phlebology 2012, 27:168-172.
• [50]Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V: "Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. Arch Immunol 2003, 60:1082-1088.
• [51]Sharp CD, Hines I, Houghton J, Warren A, Jackson TH 4th, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS: Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol 2003, 285:H2592-H2598.
• [52]Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM: Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci 1999, 112:4347-4356.
• [53]Yang Y, Rosenberg GA: MMP-mediated disruption of claudin-5 in the blood-brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 2011, 762:333-345.
• [54]Magid R, Murphy TJ, Galis ZS: Expression of matrix metalloproteinase-9 in endothelial cells is differentially regulated by shear stress. Role of c-Myc. J Biol Chem 2003, 278:32994-32999.
• [55]Cao L, Wang H, Wang F: Amyloid-β-induced matrix metalloproteinase-9 secretion is associated with retinal pigment epithelial barrier disruption. Int J Mol Med 2013, 31:1105-1112.
• [56]Carden D, Xiao F, Moak C, Willis BH, Robinson-Jackson S, Alexander S: Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol 1998, 275:H385-H392.
• [57]Hubbard RC, Ogushi F, Fells GA, Cantin AM, Jallat S, Courtney M, Crystal RG: Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of alpha 1-antitrypsin, rendering it ineffective as an inhibitor of neutrophil elastase. J Clin Invest 1987, 80:1289-1295.
• [58]Chen F, Radisky ES, Das P, Batra J, Hata T, Hori T, Baine AM, Gardner L, Yue MY, Bu G, Del Zoppo G, Patel TC, Nguyen JH: TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure. J Cereb Blood Flow Metab 2013, 33:1041-1049.
• [59]Kevil CG, Oshima T, Alexander JS: The role of p38 MAP kinase in hydrogen peroxide mediated endothelial solute permeability. Endothelium 2001, 8:107-116.
• [60]Wong V, Ching D, McCrea PD, Firestone GL: Glucocorticoid down-regulation of fascin protein expression is required for the steroid-induced formation of tight junctions and cell-cell interactions in rat mammary epithelial tumor cells. J Biol Chem 1999, 274:5443-5453.
• [61]Adams CW: Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry 1988, 51:260-265.
• [62]Adams CW, Abdulla YH, Torres EM, Poston RN: Periventricular lesions in multiple sclerosis: their perivenous origin and relationship to granular ependymitis. Neuropathol Appl Neurobiol 1987, 13:141-152.
• [63]Fog T: On the vessel–plaque relations in the brain in multiple sclerosis. Acta Neurol Scand Suppl 1963, 39:258-262.
• [64]Putnam TJ: Evidences of vascular occlusion in multiple sclerosis and encephalomyelitis. Arch Neurol Psychiatry 1937, 6:1298-1321.
• [65]Putnam TJ, Adler A: Vascular architecture of the lesions of multiple sclerosis. Arch Neurol Psychiatry 1937, 38:1-15.
• [66]Coen M, Menegatti E, Salvi F, Mascoli F, Zamboni P, Gabbiani G, Bochaton-Piallat ML: Altered collagen expression in jugular veins in multiple sclerosis. Cardiovasc Pathol 2013, 22:33-38.
• [67]Oklu R, Habito R, Mayr M, Deipolyi AR, Albadawi H, Hesketh R, Walker TG, Linskey KR, Long CA, Wicky S, Stoughton J, Watkins MT: Watkins MT Pathogenesis of varicose veins. J Vasc Interv Radiol 2012, 23:33-39.
• [68]Rathbun SW, Kirkpatrick AC: Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med 2007, 9:115-126.
• [69]Sansilvestri-Morel P, Fioretti F, Rupin A, Senni K, Fabiani JN, Godeau G, Verbeuren TJ: Comparison of extracellular matrix in skin and saphenous veins from patients with varicose veins: does the skin reflect venous matrix changes? Clin Sci (Lond) 2007, 112:229-239.
• [70]Pollman MJ, Naumovski L, Gibbons GH: Vascular cell apoptosis: cell type-specific modulation by transforming growth factor-beta1 in endothelial cells versus smooth muscle cells. Circulation 1999, 99:2019-20126.
• [71]Rodríguez-Barbero A, Obreo J, Alvarez-Munoz P, Pandiella A, Bernabéu C, López-Novoa JM: Endoglin modulation of TGF-beta1-induced collagen synthesis is dependent on ERK1/2 MAPK activation. Cell Physiol Biochem 2006, 18:135-142.
• [72]Bujan J, Gimeno MJ, Jimenez JA, et al.: Expression of elastic components in healthy and varicose veins. World J Surg 2003, 27:901-905.
• [73]Jacob T, Hingorani A, Ascher E: Overexpression of transforming growth factor-beta1 correlates with increased synthesis of nitric oxide synthase in varicose veins. J Vasc Surg 2005, 41:523-530.
• [74]Kowalewski R, Malkowski A, Sobolewski K, Gacko M: Evaluation of transforming growth factor-beta signaling pathway in the wall of normal and varicose veins. Pathobiology 2010, 77:1-6.
• [75]Pascual G, Mendieta C, Garcia-Honduvilla N, et al.: TGF-beta1 upregulation in the aging varicose vein. J Vasc Res 2007, 44:192-201.
• [76]Lal BK, Saito S, Pappas PJ, et al.: Altered proliferative responses of dermal fibroblasts to TGF-beta1 may contribute to chronic venous stasis ulcer. J Vasc Surg 2003, 37:1285-1293.
• [77]Oklu R, Walker TG, Wicky S, Hesketh R: Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol 2010, 21:1791-1805.
• [78]Pappas PJ, Lal BK, Ohara N, et al.: Regulation of matrix contraction in chronic venous disease. Eur J Vasc Endovasc Surg 2009, 38:518-529.
• [79]Yu H, Zhao G, Li H, Liu X, Wang S: Candesartan antagonizes pressure overload-evoked cardiac remodeling through Smad7 gene-dependent MMP-9 suppression. Gene 2012, 497:301-306.
• [80]MacMillan CJ, Furlong SJ, Doucette CD, Chen PL, Hoskin DW, Easton AS: Bevacizumab diminishes experimental autoimmune encephalomyelitis by inhibiting spinal cord angiogenesis and reducing peripheral T-cell responses. J Neuropathol Exp Neurol 2012, 71:983-999.
• [81]Craelius W, Migdal MW, Luessenhop CP, Sugar A, Mihalakis I: Iron deposits surrounding multiple sclerosis plaques. Arch Pathol Laboratory Med 1982, 106:397.
• [82]Haacke EM, Garbern J, Miao Y, Habib C, Liu M: Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int Angiol 2010, 29:149-157.
• [83]LeVine SM: Iron deposits in multiple sclerosis and Alzheimer’s disease brains. Brain Res 1997, 760:298-303.
• [84]Young NP, Weinshenker BG, Parisi JE, Scheithauer B, Giannini C, Roemer SF, Thomsen KM, Mandrekar JN, Erickson BJ, Lucchinetti CF: Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis. Brain 2010, 133:333-348.
• [85]Zivadinov R, Weinstock-Guttman B, Pirko I: Iron deposition and inflammation in multiple sclerosis. Which one comes first? BMC Neurosci 2011, 12:60. 1–3
• [86]Bawdier-Commander C, Verbeuren T, Lebard C, Michel JB, Jacob MP: Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathos 2000, 192:105-112.
• [87]Ono T, Bergan JJ, Schmid-Schönbein GW, Takase S: Monocyte infiltration into venous valves. J Vasc Surg 1998, 27:158-166.
• [88]Takase S, Bergan JJ, Schmid-Schönbein G: Expression of adhesion molecules and cytokines on saphenous veins in chronic venous insufficiency. Ann Vasc Surg 2000, 14:427-435.
• [89]Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B: Chronic venous disease. N Engl J Med 2006, 355:488-498.
• [90]Takase S, Schmid-Schönbein G, Bergan JJ: Leukocyte activation in patients with venous insufficiency. J Vasc Surg 1999, 30:148-156.
• [91]Powell CC, Rohrer MJ, Barnard MR, Peyton BD, Furman MI, Michelson AD: Chronic venous insufficiency is associated with increased platelet and monocyte activation and aggregation. J Vasc Surg 1999, 30:844-851.
• [92]Putnam T: Studies in multiple sclerosis: encephalitis and sclerotic plaques produced by venular obstruction. Arch of Neurol and Psych 1935, 33:929-940.
• [93]Mayhan WG, Heistad DD: Role of veins and cerebral venous pressure in disruption of the blood-brain barrier. Circ Res 1986, 59:216-220.
• [94]Youssef AM, Hamidian Jahromi A, Vijay CG, Granger DN, Alexander JS: Intra-abdominal hypertension causes reversible blood-brain barrier disruption. J Trauma Acute Care Surg 2012, 72:183-188.
• [95]Kovac N, Siranovic M, Mazul-Sunko B: Clinical significance of intra-abdominal pressure and abdominal perfusion pressure in patients with acute abdominal syndrome. SIGNA VITAE 2007, 2:14-17.
• [96]Shin HY, Smith ML, Toy KJ, Williams PM, Bizios R, Gerritsen ME: VEGF-C mediates cyclic pressure-induced endothelial cell proliferation. Physiol Genomics 2002, 11:245-251.
• [97]Shin HY, Gerritsen ME, Bizios R: Regulation of endothelial cell proliferation and apoptosis by cyclic pressure. Ann Biomed Eng 2002, 30:297-304.
• [98]Shin HY, Bizios R, Gerritsen ME: Cyclic pressure modulates endothelial barrier function. Endothelium 2003, 10:179-187.
• [99]Shin HY, Schwartz EA, Bizios R, Gerritsen ME: Receptor-mediated basic fibroblast growth factor signaling regulates cyclic pressure-induced human endothelial cell proliferation. Endothelium 2004, 11:285-291.
• [100]Miyamoto K, Tsujimoto S, Tominaga M, Takeshima T, Morimoto T, Tsunoda S, Sakaki T: The focal brain ischemia with disturbance of venous drainage]. No To Shinkei 1992, 44:621-627.
• [101]Yura S, Sako K, Yonemasu Y: [The effects of disturbance of cerebral venous drainage on focal cerebral blood flow and ischemic cerebral edema]. No To Shinkei 1990, 42:269-275.
• [102]Nedelmann M, Kaps M, Mueller-Forell W: Venous obstruction and jugular valve insufficiency in idiopathic intracranial hypertension. Journal of Neurology 2009, 256:964-969.
• [103]Meyer-Schwickerath R, Haug C, Hacker A, Fink F, Seidel D, Hartung HP, Haupts MR: Intracranial venous pressure is normal in patients with multiple sclerosis. Mult Scler 2011, 17:637-638.
• [104]Zamboni P, Bertolotto A, Boldrini P, Cenni P, D'Alessandro R, D'Amico R, Del Sette M, Galeotti R, Galimberti S, Liberati A, Massacesi L, Papini D, Salvi F, Simi S, Stella A, Tesio L, Valsecchi MG, Filippini G, Chair of the Steering Committee: Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. Trials 2012, 13:183.
• [105]Ertl-Wagner B, Koerte I, Kümpfel T, Blaschek A, Laubender RP, Schick M, Steffinger D, Kaufmann D, Heinen F, Reiser M, Alperin N, Hohlfeld R: Non-specific alterations of craniocervical venous drainage in multiple sclerosis revealed by cardiac-gated phase-contrast MRI. Mult Scler 2012, 18:1000-1007.
• [106]Koerte IK, Schankin CJ, Immler S, Lee S, Laubender RP, Grosse C, Eftimov L, Milde-Busch A, Reiser M, Straube A, Heinen F, Alperin N, Ertl-Wagner B: Altered cerebrovenous drainage in patients with migraine as assessed by phase-contrast magnetic resonance imaging. Invest Radiol 2011, 46:434-440.
• [107]Lee AB, Laredo J, Neville R: Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency. Int Angiol 2010, 29:95-108.
• [108]Sainte-Rose C, Lacombe J, Pierre-Kahn A, Renier D, Hirsch J-F: Intracranial venous sinus hypertension: cause or consequence of hydrocephalus in infants? J Neurosurg 1984, 60:727-736.
• [109]Johnston I, Owler B, Pickard J: The Pseudotumor Cerebri Syndrome. New York: Cambridge University Press; 2007.
• [110]Wall M, George D: Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991, 114:155-180.
• [111]Karahalios DG, Rekate HL, Khayata MH, Apostolides PJ: Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology 1996, 46:198-202.
• [112]Brodsky MC, Vaphiades MV: Magnetic resonance imaging in pseudotumor cerebri. Ophthalmology 1998, 105:1686-1693.
• [113]Wall M, Dollar JD, Sadun AA, Kardon R: Idiopathic intracranial hypertension. Lack of histological evidence for cerebral edema. Arch Neurol 1995, 141-145.
• [114]Karmon Y, Ramanathan M, Minagar A, Zivadinov R, Weinstock-Guttman B: Arterial, venous and other vascular risk factors in multiple sclerosis. Neurol Res 2012, 34:754-760.
• [115]Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro AF, Sheppard D, Makinen T: Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis Dev. Cell 2009, 17:175-186.
• [116]Bazigou E, Lyons OT, Smith A, Venn GE, Cope C, Brown NA, Machine T: Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J Clin Invest 2011, 121:2984-2992.
• [117]Chang CP, et al.: A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 2004, 118:649-663.
• [118]Bohlen HG, Gasheva OY, Zawieja DC: Nitric oxide formation by lymphatic bulb and valves is a major regulatory component of lymphatic pumping. Am J Physiol Heart Circ Physiol 2011, 301:H1897-H1906.
• [119]Lee TC, Zhao YD, Courtman DW, Stewart DJ: Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation 2000, 101:2345-2348.
• [120]Mellor RH, Brice G, Stanton AW, French J, Smith A, Jeffery S, Levick JR, Burnand KG: Mortimer PS; Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Lymphoedema Research Consortium. Circulation. 2007, 115:1912-1920.
• [121]Traboulsi EI, Al-Khayer K, Matsumoto M, Kimak MA, Crowe S, Wilson SE, Finegold DN, Ferrell RE, Meisler DM: Lymphedema-distichiasis syndrome and FOXC2 gene mutation. Am J Ophthalmol 2002, 134:592-596.
• [122]Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R: Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999, 13:295-306.
• [123]Dela Paz NG, D'Amore PA: Arterial versus venous endothelial cells. Cell Tissue Res 2009, 335:5-16.
• [124]Minagar A, Jy W, Jimenez JJ, Sheremata WA, Mauro LM, Mao WW, Horstman LL, Ahn YS: Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 2001, 56:1319-1324.
• [125]Alexander JS, Ganta CV, Orr AW, Funk S, Yurdagul A, Cromer W, Mathis JM, Erdreich-Epstein A, Nagra RM, Minagar A, Tsunoda I, Sato F, Martinez N, Omura S: Ephrin/Eph receptor expression on brain microvascular endothelial cells and microparticles: regulation by inflammatory cytokines. BrainPET2011. Barcelona, Spain: XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function and the Xth International Conference on Quantification of Brain Function with PET; 2011.
• [126]Akkawi NM, Agosti C, Rozzini L, Anzola GP, Padovani A: Transient global amnesia and disturbance of venous flow patterns. Lancet 2001, 357:957.
• [127]Hodges JR, Warlow CP: Syndromes of transient amnesia : towards a classification. A study of 153 cases. J Neurol Neurosurg Psychiatry 1990, 53:834-843.
• [128]Lewis SL: Aetiology of transient global amnesia. Lancet 1998, 352:397-399.
• [129]Sander D, Winbeck K, Etgen T, Knapp R, Klingelhöfer J, Conrad B: Disturbance of venous flow patterns in patients with transient global amnesia. Lancet 2000, 356:1982-1984.
• [130]Kim I, Ryu YS, Kwak HJ, Ahn SY, Oh JL, Yancopoulos GD, Gale NW, Koh GY: EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J 2002, 16:1126-1128.
• [131]Ivanov AI, Romanovsky AA: Putative dual role of ephrin-Eph receptor interactions in inflammation. IUBMB Life 2006, 58:389-394.
• [132]Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, Salvi F, Gemmati D, Liboni A, Zamboni P: Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis. BMC Med Genet 2010, 11:64.
• [133]Pirmohamed M: Genetic factors in the predisposition to drug-induced hypersensitivity reactions. AAPS Jl 2006, 8:E20-E26.
• [134]Geurts JJ, Wolswijk G, Bö L, Redeker S, Ramkema M, Troost D, Aronica E: Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions. J Neuroimmunol 2005, 158:182-190.
• [135]Anwar MA, Shalhoub J, Lim CS, Gohel MS, Davies AH: The effect of pressure-induced mechanical stretch on vascular wall differential gene expression. J Vasc Res 2012, 49:463-478.
• [136]Lightman S, McDonald WI, Bird AC, Francis DA, Hoskins A, Batchelor JR, Halliday AM: Retinal venous sheathing in optic neuritis. Its significance for the pathogenesis of multiple sclerosis. Brain 1987 Apr, 110:405-414.
• [137]Arnold AC, Pepose JS, Hepler RS, Foos RY: Retinal periphlebitis and retinitis in multiple sclerosis. I. Pathologic characteristics. Ophthalmology 1984, 91:255-262.
• [138]Engell T, Jensen OA, Klinken L: Periphlebitis retinae in multiple sclerosis. A histopathological study of two cases. Acta Ophthalmol (Copenh) 1985, 63:83-88.
• [139]Perry VH, Lund RD: Evidence that the lamina cribrosa prevents intraretinal myelination of retinal ganglion cell axons. J Neurocytol 1990, 19:265-272.
• [140]Lucarelli MJ, Pepose JS, Arnold AC, Foos RY: Immunopathologic features of retinal lesions in multiple sclerosis. Ophthalmology 1991, 98:1652-1656.
• [141]Stefansson K, Molnar ML, Marton LS, Molnar GK, Mihovilovic M, Tripathi RC, Richman DP: Myelin-associated glycoprotein in human retina. Nature 1984, 307:548-550.
• [142]Engell T, Sellebjerg F, Jensen C: Changes in the retinal veins in acute optic neuritis. Acta Neurol Scand 1999, 100:81-83.
• [143]Haselton FR, Dworska E, Evans SS, Hoffman LH, Alexander JS: Modulation of retinal endothelial barrier in an in vitro model of the retinal microvasculature. Exp Eye Res 1996, 63:211-222.
• [144]Haselton FR, Dworska EJ, Hoffman LH: Glucose-induced increase in paracellular permeability and disruption of beta-receptor signaling in retinal endothelium. Invest Ophthalmol Vis Sci 1998, 39:1676-1684.
• [145]Zamboni P, Cossu A, Carpanese L, Simonetti G, Massarelli G, Liboni A: The so-called venous aneurysms. Phlebology 1990, 5:45-50.
• [146]Callen DJ, Shroff MM, Branson HM, Li DK, Lotze T, Stephens D, Banwell BL: Role of MRI in the differentiation of ADEM from MS in children. Neurology 2009, 72:968-973.
• [147]Wingerchuk DM, Lucchinetti CF: Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol 2007, 20:343-350.
• [148]Hafler DA, Benjamin DS, Burks J, Weiner HL: Myelin basic protein and proteolipid protein reactivity of brain- and cerebrospinal fluid-derived T cell clones in multiple sclerosis and post infectious encephalomyelitis. J Immune 1987, 139:68-72.
• [149]Ichiyama T, Kajimoto M, Suenaga N, Maeba S, Matsubara T: Furukawa S Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis. J Neuroimmunol 2006, 172:182-186.
• [150]Martino D, Branson JA, Church AJ, Candler PM, Livrea P, Giovannoni G, Dale RC: Soluble adhesion molecules in acute disseminated encephalomyelitis. Pediatr Neurol 2005, 33:255-258.