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Translational Stroke Research
Published in: Translational Stroke Research 4/2011

01-12-2011 | Review Article

Vascular Pathology as a Potential Therapeutic Target in SCI

Authors: Richard L. Benton, Theo Hagg

Published in: Translational Stroke Research | Issue 4/2011

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Abstract

Acute traumatic spinal cord injury (SCI) is characterized by a progressive secondary degeneration which exacerbates the loss of penumbral tissue and neurological function. Here, we first provide an overview of the known pathophysiological mechanisms involving injured microvasculature and molecular regulators that contribute to the loss and dysfunction of existing and new blood vessels. We also highlight the differences between traumatic and ischemic injuries which may yield clues as to the more devastating nature of traumatic injuries, possibly involving toxicity associated with hemorrhage. We also discuss known species differences with implications for choosing models, their relevance and utility to translate new treatments towards the clinic. Throughout this review, we highlight the potential opportunities and proof-of-concept experimental studies for targeting therapies to endothelial cell-specific responses. Lastly, we comment on the need for vascular mechanisms to be included in drug development and non-invasive diagnostics such as serum and cerebrospinal fluid biomarkers and imaging of spinal cord pathology.
Literature
1.
Alford PW, Dabiri BE, Goss JA, Hemphill MA, Brigham MD, Parker KK. Blast-induced phenotypic switching in cerebral vasospasm. Proc Natl Acad Sci USA. 2011;108(31):12705–10 (PMID 21765001).PubMed
2.
Allen A. Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report. JAMA. 1911;57:878–80.
3.
Allen AR. Remarks on the histopathological changes in the spinal cord due to impact. An experimental study. J Nerv Ment Dis. 1914;41:141–7.
4.
Anthes DL, Theriault E, Tator CH. Ultrastructural evidence for arteriolar vasospasm after spinal cord trauma. Neurosurgery. 1996;39:804–14.PubMed
5.
Arai Y, Kubota T, Nakagawa T, Kabuto M, Sato K, Kobayashi H. Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1(PAI-1) in human brain tumors. Acta Neurochir (Wien). 1998;140:377–85.
6.
Baker KA, Hagg T. Developmental and injury-induced expression of alpha1beta1 and alpha6beta1 integins in the rat spinal cord. Brain Res. 2007;1130(1):54–66.PubMed
7.
Benton RL, Maddie MA, Dincman TA, Hagg T, Whittemore SR. Transcriptional activation of endothelial cells by TGFbeta coincides with acute microvascular plasticity following focal spinal cord ischaemia/reperfusion injury. ASN Neuro. 2009;1.
8.
Benton RL, Maddie MA, Gruenthal MJ, Hagg T, Whittemore SR. Neutralizing endogenous VEGF following traumatic spinal cord injury modulates microvascular plasticity but not tissue sparing or functional recovery. Curr Neurovasc Res. 2009;6(2):124–31.PubMed
9.
Benton RL, Maddie MA, Minnillo DR, Hagg T, Whittemore SR. Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse. J Comp Neurol. 2008;507:1031–52.PubMed
10.
Benton RL, Maddie MA, Worth CA, Mahoney ET, Hagg T, Whittemore SR. Transcriptomic screening of microvascular endothelial cells implicates novel molecular regulators of vascular dysfunction after spinal cord injury. J Cereb Blood Flow Metab. 2008;28:1771–85.PubMed
11.
Benton RL, Whittemore SR. VEGF165 therapy exacerbates secondary damage following spinal cord injury. Neurochem Res. 2003;28(11):1693–703.PubMed
12.
Benton RL, Woock JP, Gozal E, Heman M, Whittemore SR. Intraspinal application of endothelin results in focal ischemic injury of spinal gray matter and restricts the differentiation of engrafted neural stem cells. Neurochem Res. 2005;30(6–7):809–23.PubMed
13.
Bilgen M, Al-Hafez B, Alrefae T, He YY, Smirnova IV, Aldur MM, et al. Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response. Magn Reson Imaging. 2007;25:657–64.PubMed
14.
Blasi F, Sidenius N. The urokinase receptor: focused cell surface proteolysis, cell adhesion and signaling. FEBS Lett. 2010;584(9):1923–30.PubMed
15.
Boado RJ, Hui EK, Lu JZ, Zhou QH, Pardridge WM. Reversal of lysosomal storage in brain of adult MPS-1 mice with intravenous trojan horse-iduronidase fusion protein. Mol Pharm. 2011;8(4):1342–50.PubMed
16.
Boado RJ, Pardridge. Glucose deprivation causes post-transcriptional enhancement of brain capillary endothelial glucose transporter gene expression via GLUT1 mRNA stabilization. J Neurochem. 1993;60:2290–6.PubMed
17.
Boado RJ, Pardridge WM. Comparison of blood-brain barrier transport of glial-derived neurotrophic factor (GDNF) and an IgG-GDNF fusion protein in the rhesus monkey. Drug Metab Dispos. 2009;37(12):2299–304.PubMed
18.
Boado RJ, Zhang Y, Zhang Y, Pardridge WM. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol Bioeng. 2007;96(2):381–91.PubMed
19.
Boas DA, Dunn AK. Laser speckle contrast imaging in biomedical optics. J Biomed Opt. 2010;15:011109.PubMed
20.
Bogaert L, Scheller D, Monnen J, Sarre S, Smolders I, Ebinger G, et al. Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia. Brain Res. 2000;887(2):266–75.PubMed
21.
Bogousslavsky J, Victor SJ, Salinas EO, Pallay A, Donnan GA, Fieschi C, et al. Fiblast (trafermin) in acute stroke: results of the European-Australian phase II/III safety and efficacy trial. Cerebrovasc Dis. 2002;14(3–4):239–51.PubMed
22.
Bramlett HM, Dietrich WD. Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res. 2007;161:125–41.PubMed
23.
Budde MD, Xie M, Cross AH, Song SK. Axial diffusivity is the primary correlate of axonal injury in the experimental autoimmune encephalomyelitis spinal cord: a quantitative pixelwise analysis. J Neurosci. 2009;29:2805–13.PubMed
24.
Byrnes KR, Fricke ST, Faden AI. Neuropathological differences between rats and mice after spinal cord injury. J Magn Reson Imaging. 2010;32:836–46.PubMed
25.
Byrnes KR, Garay J, Di Giovanni S, De Biase A, Knoblach SM, Hoffman EP, et al. Expression of two temporally distinct microglia-related gene clusters after spinal cord injury. Glia. 2006;53:420–33.PubMed
26.
Casella GT, Bunge MB, Wood PM. Endothelial cell loss is not a major cause of neuronal and glial cell death following contusion injury of the spinal cord. Exp Neurol. 2006;202:8–20.PubMed
27.
Casella GT, Marcillo A, Bunge MB, Wood PM. New vascular tissue rapidly replaces neural parenchyma and vessels destroyed by a contusion injury to the rat spinal cord. Exp Neurol. 2002;173:63–76.PubMed
28.
Chen A, Springer JE. Neuroproteomic methods in spinal cord injury. Mehods Mol Biol. 2009;566:57–67.
29.
Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 2003;23(24):8568–77.PubMed
30.
Chou PC, Shunmugavel A, El Sayed H, Desouki MM, Nguyen SA, Khan M, et al. Preclinical use of longitudinal MRI for screening the efficacy of S-nitrosoglutathione in treating spinal cord injury. J Magn Reson Imaging. 2011;33:1301–11.PubMed
31.
Coomber BL, Stewart PA. Three-dimensional reconstruction of vesicles in endothelium of blood-brain barrier versus highly permeable microvessels. Anat Rec. 1986;215(3):256–61.PubMed
32.
Corada M, Zanetta L, Orsenigo F, Breviario F, Lampugnani MG, Bernasconi S, et al. A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood. 2002;100(3):905–11.PubMed
33.
Davalos D, Lee JK, Smith WB, Brinkman B, Ellisman MH, Zheng B, et al. Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods. 2008;169:1–7.PubMed
34.
Deng G, Curriden SA, Hu G, Czekay RP, Loskutoff DJ. Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin. J Cell Physiol. 2001;189(1):23–33.PubMed
35.
De Biase A, Knoblach SM, Di Giovanni S, Fan C, Molon A, Hoffman EP, et al. Gene expression profiling of experimental traumatic spinal cord injury as a function of distance from impact site and injury severity. Physiol Genomics. 2005;22:368–81.PubMed
36.
Di Giovanni S, Knoblach SM, Brandoli C, Aden SA, Hoffman EP, Faden AI. Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol. 2003;53:454–68.PubMed
37.
Dohrmann GJ, Allen WE. Microcirculation of traumatized spinal cord. A correlation of microangiography and blood flow patterns in transitory and permanent paraplegia. J Trauma. 1975;15:1003–13.PubMed
38.
Dohrmann GJ, Wick KM. Demonstration of the microvasculature of the spinal cord by intravenous injection of the fluorescent dye, thioflavine S. Stain Technol. 1971;46:321–2.PubMed
39.
Dray C, Rougon G, Debarbieux F. Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord. Proc Natl Acad Sci U S A. 2009;106:9459–64.PubMed
40.
Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, et al. Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol. 2001;24:254–64.PubMed
41.
Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal barriers: function and dysfunction. Semin Immunopathology. 2009;31(4):497–511.
42.
Enzmann GU, Benton RL, Woock JP, Howard RM, Tsoulfas P, Whittemore SR. Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord. Exp Neurol. 2005;195(2):293–304.PubMed
43.
Ehrlich P. Uber die beziehung chemischer constitution, vertheilung, and pharmakologischer wirkung. Berlin: Wiley; 1904.
44.
Eppihimer MJ, Wolitzky B, Anderson DC, Labow MA, Granger DN. Heterogeneity of expression of E- and P-selectins in vivo. Circ Res. 1996;79(3):560–9.PubMed
45.
Fassbender JM, Myers SA, Whittemore SR. Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery. Exp Neurol. 2011;227:302–13.PubMed
46.
Fassbender JM, Whittemore SR, Hagg T. Targeting microvasculature for neuroprotection after SCI. Neurotherapeutics. 2011;8:240–51.PubMed
47.
Fehlings MG, Tator CH, Linden RD. The effect of nimodipine and dextran on axonal function and blood flow following experimental spinal cord injury. J Neurosurg. 1989;71:403–16.PubMed
48.
Fisher M, Meadows ME, Do T, Weise J, Trubetskoy V, Charette M, et al. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1995;15(6):953–9.PubMed
49.
Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE, Saenz AD, et al. The cellular inflammatory response in human spinal cords after injury. Brain. 2006;129(12):3249–69.PubMed
50.
Fu A, Hui EK, Lu JZ, Boado RJ, Pardridge WM. Neuroprotection in experimental stroke in the rat with an IgG-erythropoietin fusion protein. Brain Res. 2010;1360:193–7.PubMed
51.
Fukumura D, Duda DG, Munn LL, Jain RK. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation. 2010;17:206–25.PubMed
52.
Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6 pt 2):1777–88.PubMed
53.
Gandhi RR, Bell DR. Importance of charge on transvascular albumin transport in skin and skeletal muscle. Am J Physiol. 1992;262(4pt2):H999–H1008.PubMed
54.
Gerzanich V, Woo SK, Vennekens R, Tsymbalyuk O, Ivanova S, Ivanov A, et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med. 2009;15:185–91.PubMed
55.
Glezer I, Chernomoretz A, David S, Plante MM, Rivest S. Genes involved in the balance between neuronal survival and death during inflammation. PLoS One. 2007;2:e310.PubMed
56.
Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science. 2011;333(6039):238–42.PubMed
57.
Gramling MW, Church FC. Plasminogen activator inhibitor-1 is an aggregate response factor with pleiotropic effects on cell signaling in vascular disease and the tumor microenvironment. Thromb Res. 2010;125(5):377–81.PubMed
58.
Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA, et al. Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci. 2004;24(16):4043–51.PubMed
59.
Grobelny D, Poncz L, Galardy RE. Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992;31:7152–4.PubMed
60.
Guha A, Tator CH, Smith CR, Piper I. Improvement in post-traumatic spinal cord blood flow with a combination of a calcium channel blocker and a vasopressor. J Trauma. 1989;29:1440–7.PubMed
61.
Guth L, Zhang Z, Steward O. The unique histopathological responses of the injured spinal cord. Implications for neuroprotective therapy. Ann N Y Acad Sci. 1999;890:366–84.PubMed
62.
Hagg T, Oudega M. Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma. 2006;23:264–80.PubMed
63.
Hall ED, Springer JE. Neuroprotection and acute spinal cord injury: a reappraisal. NeuroRx. 2004;1:80–100.PubMed
64.
Hamann GF, Burggraf D, Martens HK, Liebetrau M, Jager G, Wunderlich N, et al. Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia. Stroke. 2004;35:764–9.PubMed
65.
Han S, Arnold SA, Sithu SD, Mahoney ET, Geralds JT, Tran P, et al. Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury. Brain. 2010;133:1026–42.PubMed
66.
Hardebo JE, Kahrstom J. Endothelial negative surface charge areas and blood-brain barrier function. Acta Physiol Scand Suppl. 1985;125(3):495–9.
67.
Herrera JJ, Sundberg LM, Zentilin L, Giacca M, Narayana PA. Sustained expression of vascular endothelial growth factor and angiopoietin-1 improves blood-spinal cord barrier integrity and functional recovery after spinal cord injury. J Neurotrauma. 2010;27:2067–76.PubMed
68.
Hildenbrand R, Gandhari M, Stroebel P, Marx A, Allgayer H, Arens N. The urokinase-system role of cell proliferation and apoptosis. Histol Histopathol. 2008;23(2):227–36.PubMed
69.
Jakeman LB, Guan Z, Wei P, Ponnappan R, Dzwonczyk R, Popovich PG, et al. Traumatic spinal cord injury produced by controlled contusion in mouse. J Neurotrauma. 2000;17(4):299–319.PubMed
70.
Kakulas BA. Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord. 2004;42(10):549–63.PubMed
71.
Kanno H, Ozawa H, Dohi Y, Sekiguchi A, Igarashi K, Itoi E. Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice. J Neurotrauma. 2009;26:31–9.PubMed
72.
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.PubMed
73.
Kim JH, Loy DN, Wang Q, Budde MD, Schmidt RE, Trinkaus K, et al. Diffusion tensor imaging at 3 h after traumatic spinal cord injury predicts long-term locomotor recovery. J Neurotrauma. 2010;27:587–98.PubMed
74.
Kimura A, Hsu M, Seldin M, Verkman AS, Scharfman HE, Binder DK. Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann Neurol. 2010;67(6):794–801.PubMed
75.
King LS, Agre P. Pathophysiology of the aquaporin water channels. Annu Rev Physiol. 1996;58:619–48.PubMed
76.
Klein T, Bischoff R. Active metalloproteases of the A Disintegrin and Metalloprotease (ADAM) family: biological function and structure. J Proteome Res. 2011;10:17–33.PubMed
77.
Kwon BK, Casha S, Hurlbert RJ, Yong VW. Inflammatory and structural biomarkers in acute traumatic spinal cord injury. Clin Chem Lab Med. 2011;49(3):425–33.PubMed
78.
Kwon BK, Stammers AM, Belanger LM, Bernardo A, Chan D, Bishop CM, et al. Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury. J Neurotrauma. 2010;27(4):669–82.PubMed
79.
Lawler J, Detmar M. Tumor progression: the effects of thrombospondin-1 and-2. Int J Biochem Cell Biol. 2004;36(6):1038–45.PubMed
80.
Lawrenson JG, Reid AR, Allt G. Molecular characteristics of pial microvessels of the rat optic nerve. Can pial microvessels be used as a model for the blood-brain barrier? Cell Tissue Res. 1997;288(2):259–65.PubMed
81.
Lee ME, Bloch KD, Clifford JA, Quertermous T. Functional analysis of the endothelin-1 gene promoter. Evidence for an endothelial cell-specific cis-acting sequence. J Biol Chem. 1990;265(18):10446–50.
82.
Lin Y, Vreman HJ, Wong RJ, Tjoa T, Yamauchi T, Noble-Haeusslein LJ. Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord. J Cereb Blood Flow Metab. 2007;27:1010–21.PubMed
83.
Loy DN, Crawford CH, Darnall JB, Burke DA, Onifer SM, Whittemore SR. Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat. J Comp Neurol. 2002;445:308–24.PubMed
84.
Loy DN, Sroufe AE, Pelt JL, Burke DA, Cao QL, Talbott JF, et al. Serum biomarkers for experimental acute spinal cord injury: rapid elevation of neuron-specific enolase and S-100beta. Neurosurgery. 2005;56(2):391–7.PubMed
85.
Lubieniecka JM, Streijger F, Lee JH, Stoynov N, Liu J, Mottus R, et al. Biomarkers for severity of spinal cord injury in the cerebrospinal fluid of rats. PLoS One. 2011;6(4):e19247.PubMed
86.
Ma M, Basso DM, Walters P, Stokes BT, Jakeman LB. Behavioral and histological outcomes following graded spinal cord contusion injury in the C57Bl/6 mouse. Exp Neurol. 2001;169(2):239–54.PubMed
87.
Macrae IM, Robinson MJ, Graham DI, Reid JL, McCulloch J. Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J Cereb Blood Flow Metab. 1993;13(2):276–84.PubMed
88.
Mahoney ET, Benton RL, Maddie MA, Whittemore SR, Hagg T. ADAM8 is selectively up-regulated in endothelial cells and is associated with angiogenesis after spinal cord injury in adult mice. J Comp Neurol. 2009;512:243–55.PubMed
89.
Matz P, Turner C, Weinstein PR, Massa SM, Panter SS, Sharp FR. Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage. Brain Res. 1996;713:211–22.PubMed
90.
Matz PG, Fujimura M, Chan PH. Subarachnoid hemolysate produces DNA fragmentation in a pattern similar to apoptosis in mouse brain. Brain Res. 2000;858:312–9.PubMed
91.
Mautes AE, Kim DH, Sharp FR, Panter S, Sato M, Maida N, et al. Induction of heme oxygenase-1 (HO-1) in the contused spinal cord of the rat. Brain Res. 1998;795:17–24.PubMed
92.
Mautes AE, Weinzierl MR, Donovan F, Noble LJ. Vascular events after spinal cord injury: contribution to secondary pathogenesis. Phys Ther. 2000;80:673–87.PubMed
93.
McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med. 2003;9:713–25.PubMed
94.
McKenzie AL, Hall JJ, Aihara N, Fukuda K, Noble LJ. Immunolocalization of endothelin in the traumatized spinal cord: relationship to blood-spinal cord barrier breakdown. J Neurotrauma. 1995;12(3):257–68.PubMed
95.
Means ED, Anderson DK, Nicolosi G, Gaudsmith J. Microvascular perfusion experimental spinal cord injury. Surg Neurol. 1978;9:353–60.PubMed
96.
Milner RDG. Fat and carbohydrate metabolism. In: Glukman PD, Heyman MA, editors. Pediatrics and perinatology, the scientific basis. London: Arnold; 1996. p. 447–50.
97.
Mostany R, Portera-Cailliau C. A method for 2-photon imaging of blood flow in the neocortex through a cranial window. J Vis Exp. 2008;678. doi:10.​3791/​678.
98.
Mozer AB, Whittemore SR, Benton RL. Spinal expression of PV-1 is associated with inflammation, perivascular astrocyte loss, and diminished EC glucose transport potential in acute SCI. Curr Microvasc Res. 2010;7(3):238–50.
99.
Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, et al. Sequence and structure of a human glucose transporter. Science. 1985;229:941–5.PubMed
100.
Myers SA, DeVries WH, Andres KR, Gruenthal MJ, Benton RL, Hoying JB, et al. CD47 knockout mice exhibit improved recovery from spinal cord injury. Neurobiol Dis. 2011;42:21–34.PubMed
101.
Nagai N, Okada K, Kawao N, Ishida C, Ueshima S, Collen D, et al. Urokinase-type plasminogen activator receptor (uPAR) augments brain damage in a murine model of ischemic stroke. Neurosci Lett. 2008;432:46–9.PubMed
102.
Nelson E, Gertz SD, Rennels ML, Ducker TB, Blaumanis OR. Spinal cord injury. The role of vascular damage in the pathogenesis of central hemorrhagic necrosis. Arch Neurol. 1977;34:332–3.PubMed
103.
Nesic O, Guest JD, Zivadinovic D, Narayana PA, Herrera JJ, Grill RJ, et al. Aquaporins in spinal cord injury: the janus face of aquaporin 4. Neuroscience. 2010;168(4):1019–35.PubMed
104.
Nesic O, Lee J, Johnson KM, Ye Z, Xu GY, Unabia GC, et al. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J Neurochem. 2005;95:998–1014.PubMed
105.
Nesic O, Lee J, Ye Z, Unabia GC, Rafati D, Hulsebosch CE, et al. Acute and chronic changes in aquaporin 4 expression after spinal cord injury. Neuroscience. 2006;143(3):779–92.PubMed
106.
Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, et al. Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice. Glia. 2003;42(3):235–51.PubMed
107.
Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. 2003;161(3):653–60.
108.
Niwa M, Kawaguchi T, Himeno A, Fujimoto M, Kurihara M, Yamashita K, et al. Specific binding sites for 125I-endothelin-1 in the porcine and human spinal cord. Eur J Pharmacol. 1992;225(4):281–9.PubMed
109.
Noble LJ, Cortez SC, Ellison JA. Endogenous peroxidatic activity in astrocytes after spinal cord injury. J Comp Neurol. 1990;296:674–85.PubMed
110.
Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci. 2002;22:7526–35.PubMed
111.
Noble LJ, Mautes AE, Hall JJ. Characterization of the microvascular glycocalyx in normal and injured spinal cord in the rat. J Comp Neurol. 1996;376:542–56.PubMed
112.
Noble LJ, Wrathall JR. Spinal cord contusion in the rat: morphometric analyses of alterations in the spinal cord. Exp Neurol. 1985;88(1):135–49.PubMed
113.
Noble LJ, Wrathall JR. Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage. Exp Neurol. 1988;99(3):567–78.
114.
Noble LJ, Wrathall JR. Correlative analyses of lesion development and functional status after graded spinal cord contusive injuries in the rat. Exp Neurol. 1989;103:34–40.PubMed
115.
Noble LJ, Wrathall JR. Distribution and time course of protein extravasation in the rat spinal cord after contusive injury. Brain Res. 1989;482:57–66.PubMed
116.
Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: defining the problems. J Neurotrauma. 2004;21:429–40.PubMed
117.
Nunes SS, Krishnan L, Gerard CS, Dale JR, Maddie MA, Benton RL, et al. Angiogenic potential of microvessel fragments is independent of the tissue of origin and can be influenced by the cellular composition of the implants. Microcirculation. 2010;17(7):557–67.PubMed
118.
Ogawa T, Hanggi D, Wu Y, Michiue H, Tomizawa K, Ono S, et al. Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2011. doi:10.​1038/​jcbfm.​2011.​87.
119.
Ohtsuki S, Terasaki T. Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain: importance for CNS drug discovery and development. Pharm Res. 2007;24(9):1745–58.PubMed
120.
Pardridge WM. Brain drug development and brain drug targeting. Pharm Res. 2007;24(9):1729–32.PubMed
121.
Pardridge WM, Kang YS, Buciak JL, Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm Res. 1995;12(6):807–16.PubMed
122.
Peters BP, Goldstein IJ. The use of fluorescein-conjugated Bandeiraea simplicifolia B4-isolectin as a histochemical reagent for the detection of alpha-D-galactopyranosyl groups. Their occurrence in basement membranes. Exp Cell Res. 1979;120(2):321–34.PubMed
123.
Pointillart V, Petitjean ME, Wiart L, Vital JM, Lassie P, Thicoipe M, et al. Pharmacological therapy of spinal cord injury during the acute phase. Spinal Cord. 2000;38:71–6.PubMed
124.
Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol. 1999;158:351–65.PubMed
125.
Popovich PG, Lemeshow S, Gensel JC, Tovar CA. Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury. Exp Neurol. 2010. doi:10.​1016/​j.​expneurol.​2010.​11.​016 (PMID 21145891).
126.
Qian J, Herrera JJ, Narayana PA. Neuronal and axonal degeneration in experimental spinal cord injury: in vivo proton magnetic resonance spectroscopy and histology. J Neurotrauma. 2010;27:599–610.PubMed
127.
Rathore KI, Kerr BJ, Redensek A, Lopez-Vales R, Jeong SY, Ponka P, et al. Ceruloplasmin protects injured spinal cord from iron-mediated oxidative damage. J Neurosci. 2008;28:12736–47.PubMed
128.
Reiss K, Saftig P. The “a disintegrin and metalloprotease” (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol. 2009;20:126–37.PubMed
129.
Ross IB, Tator CH, Theriault E. Effect of nimodipine or methylprednisolone on recovery from acute experimental spinal cord injury in rats. Surg Neurol. 1993;40:461–70.PubMed
130.
Saadoun S, Bell BA, Verkman AS, Papadopoulos MC. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain. 2008;131(4):1087–98.PubMed
131.
Sadrzadeh SM, Anderson DK, Panter SS, Hallaway PE, Eaton JW. Hemoglobin potentiates central nervous system damage. J Clin Invest. 1987;79:662–4.PubMed
132.
Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Ciol Cell. 2000;11(12):4131–42.
133.
Salzman SK, Acosta R, Beck G, Madden J, Boxer B, Ohlstein EH. Spinal endothelin content is elevated after moderate local trauma in the rat to levels associated with locomotor dysfunction after intrathecal injection. J Neurotrauma. 1996;13(2):93–101.PubMed
134.
Schmitt M, Janicke F, Moniwa N, Chucholowski N, Pache L, Graeff H. Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. Biol Chem Hoppe Seyler. 1992;373(7):611–22.PubMed
135.
Schwartz G, Fehlings MG. Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg. 2001;94:245–56.PubMed
136.
Sehba FA, Friedrich V. Early micro vascular changes after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110:49–55.PubMed
137.
Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, et al. Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12(4):433–0.PubMed
138.
Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C, Melnichenko L, et al. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2009;29:317–30.PubMed
139.
Simard JM, Tsymbalyuk O, Ivanov A, Ivanova S, Bhatta S, Geng Z, et al. Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J Clin Invest. 2007;117:2105–13.PubMed
140.
Simard JM, Woo SK, Norenberg MD, Tosun C, Chen Z, Ivanova S, et al. Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma. Sci Transl Med. 2010;2:28ra–9ra.
141.
Smith DE, Johanson CE, Keep RF. Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Deliv Rev. 2004;56(12):1765–91.PubMed
142.
Song BW, Vinters HV, Wu D, Pardridge WM. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J Pharmacol Exp Ther. 2002;301(2):605–10.PubMed
143.
Sroga JM, Jones TB, Kigerl KA, McGaughy VM, Popovich PG. Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J Comp Neurol. 2003;462(2):223–40.PubMed
144.
Stark B, Carlstedt T, Cullheim S, Risling M. Developmental and lesion-induced changes in the distribution of the glucose transporter Glut-1 in the central and peripheral nervous system. Exp Brain Res. 2000;131:74–84.PubMed
145.
Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.PubMed
146.
Sundberg LM, Herrera JJ, Narayana PA. Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment. J Neurotrauma. 2011;28:565–78.PubMed
147.
Suzuki R, Masaoka H, Hirata Y, Marumo F, Isotani E, Hirakawa K. The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurismal subarachnoid hemorrhage. J Neurosurg. 1992;77(1):96–100.PubMed
148.
Swanson JA, Kern DF. Characterization of pulmonary endothelial charge barrier. Am J Physiol. 1994;266(4 pt 2):H1300–3.PubMed
149.
Taddei A, Giampietro C, Conti A, Orsenigo F, Breviario F, Pirazzoli V, et al. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol. 2008;10(8):923–34.PubMed
150.
Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Erythrocyte/HepG2-type glucose transporter is concentrated in cells of blood-tissue barriers. Biochem Biophys Res Commun. 1990;173:67–73.PubMed
151.
Tatar I, Chou PC, Desouki MM, El Sayed H, Bilgen M. Evaluating regional blood spinal cord barrier dysfunction following spinal cord injury using longitudinal dynamic contrast-enhanced MRI. BMC Med Imaging. 2009;9:10.PubMed
152.
Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991;75:15–26.PubMed
153.
Uesugi M, Kasuya Y, Hama H, Yamamoto M, Hayashi K, Masaki T, et al. Endogenous endothelin-1 initiates astrocytic growth after spinal cord injury. Brain Res. 1996;728(2):255–9.PubMed
154.
Uesugi M, Kasuya Y, Hayashi K, Goto K. SB209670, a potent endothelin receptor antagonist, prevents or delays axonal degeneration after spinal cord injury. Brain Res. 1998;786(1–2):235–9.PubMed
155.
Vakoc BJ, Lanning RM, Tyrrell JA, Padera TP, Bartlett LA, Stylianopoulos T, et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med. 2009;15:1219–23.PubMed
156.
van Laar PJ, van der Grond J, Hendrikse J. Brain perfusion territory imaging: methods and clinical applications of selective arterial spin-labeling MR imaging. Radiology. 2008;246:354–64.PubMed
157.
Varma MV, Khandavilli S, Ashokraj Y, Jain A, Dhanikula A, Sood A, et al. Biopharmaceutic classification system: a scientific framework for pharmacokinetic optimization in drug research. Curr Drug Metab. 2004;5(5):375–88.PubMed
158.
Vatter H, Konczalla J, Seifert V. Endothelin related pathophysiology in cerebral vasospasm: what happens to the cerebral vessels? Acta Neurochir Suppl. 2011;110:177–80.PubMed
159.
Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, et al. Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neruobiol Dis. 2009;36(1):200–12.
160.
Vorbrodt AW. Ultracytochemical characterization of anionic sites in the wall of brain capillaries. J Neurocytology. 1989;18(3):359–68.
161.
Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, et al. Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem. 2002;45(1):219–32.PubMed
162.
Wagner Jr FC, Van Gilder JC, Dohrmann GJ. The development of intramedullary cavitation following spinal cord injury: an experimental pathological study. Paraplegia. 1977;14:245–50.PubMed
163.
Weaver LC, Gris D, Saville LR, Oatway MA, Chen Y, Marsh DR, et al. Methylprednisolone causes minimal improvement after spinal cord injury in rats, contrasting with benefits of an anti-integrin treatment. J Neurotrauma. 2005;22:1375–87.PubMed
164.
Wells JE, Rice TK, Nuttall RK, Edwards DR, Zekki H, Rivest S, et al. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci. 2003;23(31):10107–15.PubMed
165.
Whetstone WD, Hsu JY, Eisenberg M, Werb Z, Noble-Haeusslein LJ. Blood-spinal cord barrier after spinal cord injury: relation to revascularization and wound healing. J Neurosci Res. 2003;74(2):227–39.PubMed
166.
Wu D, Pardridge WM. Pharmacokinetics and blood-brain barrier transport of an anti-transferrin receptor monoclonal antibody (OX26) in rats after chronic treatment with the antibody. Drug Metab Dispos. 1998;26(9):937–9.PubMed
167.
Wuestenfeld JC, Herold J, Niese U, Kappert U, Schmeisser A, Strasser RH, et al. Indocyanine green angiography: a new method to quantify collateral flow in mice. J Vasc Surg. 2008;48:1315–21.PubMed
168.
Xing C, Lee S, Kim WJ, Wnag H, Yang YG, Ning M, et al. Neurovascular effects of CD47 signaling: promotion of cell death, inflammation, and suppression of angiogenesis in brain endothelial cell in vitro. J Neurosci Res. 2009;87(11):2571–7.PubMed
169.
Yamauchi T, Lin Y, Sharp FR, Noble-Haeusslein LJ. Hemin induces heme oxygenase-1 in spinal cord vasculature and attenuates barrier disruption and neutrophil infiltration in the injured murine spinal cord. J Neurotrauma. 2004;21:1017–30.PubMed
170.
171.
Yang P, Baker KA, Hagg T. The ADAMs family: coordinators of nervous system development, plasticity and repair. Prog Neurobiol. 2006;79:73–94.PubMed
172.
Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med. 2006;203(6):1447–58.PubMed
173.
Yong VW, Agrawal SM, Stirling DP. Targeting MMPs in acute and chronic neurological conditions. Neurotherapeutics. 2007;4:580–9.PubMed
174.
Yu F, Kamada H, Miizuma K, Endo H, Chan PH. Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma. 2008;25:184–95.PubMed
175.
Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ. Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist. 2010;16:156–70.PubMed
176.
Zhang H, Chang M, Hansen CN, Basso DM, Noble-Haeusslein LJ. Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics. 2011;8:206–20.PubMed
177.
Zhang KH, Xiao HS, Lu PH, Shi J, Li GD, Wang YT, et al. Differential gene expression after complete spinal cord transection in adult rats: an analysis focused on a subchronic post-injury stage. Neuroscience. 2004;128:375–88.PubMed
178.
Zhang M, Zhu GY, Gao HY, Zhao SP, Xue Y. Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in gastric adenocarcinoma. J Surg Oncol. 2011;103:243–7.PubMed
179.
Zhang X, Lawler J. Thrombospondin-based antiangiogenic therapy. Microvasc Res. 2007;74(2–3):90–9.PubMed
180.
Zhang Y, Pardridge WM. Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke. 2001;32(6):1378–84.PubMed
181.
Zhang ZG, Chopp M, Goussev A, Lu D, Morris D, Tsang W, et al. Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats. J Neurosci. 1999;19:10898–907.PubMed
182.
Zhao H, Webb RH, Ortel B. Review of noninvasive methods for skin blood flow imaging in microcirculation. J Clin Eng. 2002;27:40–7.
183.
Zhou Y, Martin RD, Zhang JH. Advances in experimental subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110:15–21.PubMed
Metadata
Title
Vascular Pathology as a Potential Therapeutic Target in SCI
Authors
Richard L. Benton
Theo Hagg
Publication date
01-12-2011
Publisher
Springer-Verlag
Published in
Translational Stroke Research / Issue 4/2011
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-011-0128-7

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