TPA and proteolysis in the neurovascular unit.

Abstract

HomeStrokeVol. 35, No. 2tPA and Proteolysis in the Neurovascular Unit Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBtPA and Proteolysis in the Neurovascular Unit Eng H. Lo, PhD, Joseph P. Broderick, MD and Michael A. Moskowitz, MD Eng H. LoEng H. Lo From the Neuroprotection Research Laboratory (E.H.L.), Departments of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Mass; Department of Neurology (J.P.B.), University of Cincinnati, Cincinnati, Ohio; and Neurovascular Regulation and Stroke Laboratory (M.A.M.), Departments of Radiology and Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. Search for more papers by this author , Joseph P. BroderickJoseph P. Broderick From the Neuroprotection Research Laboratory (E.H.L.), Departments of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Mass; Department of Neurology (J.P.B.), University of Cincinnati, Cincinnati, Ohio; and Neurovascular Regulation and Stroke Laboratory (M.A.M.), Departments of Radiology and Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. Search for more papers by this author and Michael A. MoskowitzMichael A. Moskowitz From the Neuroprotection Research Laboratory (E.H.L.), Departments of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Mass; Department of Neurology (J.P.B.), University of Cincinnati, Cincinnati, Ohio; and Neurovascular Regulation and Stroke Laboratory (M.A.M.), Departments of Radiology and Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. Search for more papers by this author Originally published1 Feb 2004https://doi.org/10.1161/01.STR.0000115164.80010.8AStroke. 2004;35:354–356One of the major recommendations emerging from the NINDS Stroke Progress Review Group was to shift the emphasis from a purely neurocentric view of cell death toward a more integrative approach whereby responses in all brain cells and matrix are considered during cerebral ischemia (see Figure). The concept of the neurovascular unit (fundamentally comprising endothelium, astrocyte, and neuron) provides a modular framework where cell-cell signaling and cell-matrix interactions mediate the overall tissue response to stroke and its treatments.1 There is no doubt that reperfusing blood vessels mechanically or pharmacologically prevents cell death and rescues brain when performed in a timely manner, as it does in ischemic myocardium. However, under some circumstances, thrombolysis and reperfusion lead to cerebral hemorrhage and edema. Here, we examine the hypothesis that beneficial versus potentially deleterious outcomes after tissue plasminogen activator (tPA) stroke therapy may relate in part to matrix proteolysis within the neurovascular unit, and review recent advances in this area. Download figureDownload PowerPointSchematic of the basic neurovascular unit showing functional interactions between neuron, astrocyte, and cerebral endothelium. This conceptual construct provides a framework for investigating the integrative response of brain to stroke and therapy. Note: ultimately, all cell types should be considered including smooth muscle cells, pericytes, as well as oligodendrocytes and axons in white matter.tPA: More Than Clot LysisMore than 7 years after the major ECASS and NINDS trials,2,3 use of tPA therapy remains limited.4 In part, this may be due to narrow time-to-treatment windows and apparent complications of hemorrhage and brain injury.5 The primary action of tPA occurs inside the blood vessel. But what happens when tPA reperfusion occurs within the context of weakened vessels and perturbed neurovascular homeostasis? Although unequivocal human data are lacking, findings from animal models suggest that possibly deleterious consequences of tPA reperfusion may develop because tPA is more than just a clot buster. Tsirka, Strickland, Lipton and colleagues first demonstrated that tPA knockout mice are protected against kainic acid hippocampal injury and focal cerebral ischemia.6,7 Subsequently, it was shown that tPA may interact with the NR1 subunit of the NMDA receptor complex, thus amplifying damaging calcium currents during ischemic excitotoxicity.8 tPA (and plasmin) may also target nonfibrin substrates in brain extracellular matrix. For example, tPA amplifies excitotoxic neuron death in the hippocampus by degrading interneuronal laminin and disrupting pro-survival cell-matrix signaling.9 Another recent study showed that administering a chemical antagonist or deleting the gene of the protease activated receptor-1 (PAR-1) significantly reduced infarction after focal ischemia.10 Although the main effect of tPA in stroke certainly occurs within the targeted vessel, these findings suggest that extravascular actions of tPA may complicate its intended role in clot lysis. Reperfusion of ischemic brain is clearly beneficial. But a deeper understanding of how tPA also affects neurovascular matrix may reveal new approaches to further improve tPA thrombolysis.tPA and Matrix MetalloproteinasesExtracellular proteolysis in brain is an important physiological phenomenon required for cell migration, and neurite and axon extension during brain development and plasticity. Besides tPA, matrix metalloproteinases (MMPs) comprise the other major proteolytic system in mammalian brain.11,12 MMPs are important mediators in stroke because they are upregulated after ischemia, and subsequently degrade critical components of the neurovascular matrix and blood-brain barrier. Degradation of basal lamina substrates, blood-brain barrier leakage, edema, and infarction are reduced in MMP-9 knockout mice after focal cerebral ischemia.13 Hippocampal neuronal death is reduced in MMP-9 knockouts after transient global cerebral ischemia.14Can some of the deleterious side effects of tPA be caused by tPA-induced MMP upregulation?15 In rat embolic stroke models, clot lysis with tPA increases ischemic brain MMP-9 levels, and co-treatment with MMP inhibitors reduced tPA-induced hemorrhagic transformation and brain injury.16,17 The “tPA-induced MMP-9” hypothesis is further supported by a study showing that after focal cerebral ischemia, MMP-9 levels are lower in tPA knockout mice compared with wild-type mice.18 But how does tPA amplify MMP-9? In part, it may be nonspecifically related to oxidative stress induced by reperfusion injury because the MMP-9 gene promoter possesses NFkB transcription factor sites.18 However, more specific signaling mechanisms may also be involved; tPA is now recognized as a cell-signaling molecule in neurons and glia.19,20 Although the precise signaling mechanisms remain to be fully elucidated, recent studies suggest a role for the low-density lipoprotein receptor related protein (LRP), a member of the large lipoprotein receptor gene family that is already implicated in vascular correlates of ApoE and amyloid processing. LRP is enriched in brain, possesses cell signaling properties, and avidly binds tPA.21 In human brain endothelial cells, addition of recombinant tPA upregulated MMP-9 mRNA and protein, whereas this tPA-induced MMP-9 response was decreased in endothelial cells treated with RNAi to suppress LRP, and in MEF cells deficient in LRP expression.18 Direct intraventricular injections of tPA into mouse brain increased blood-brain barrier permeability, and this response was ameliorated by LRP antagonists.22 These data suggest that a specific receptor signaling pathway may trigger dysregulated proteolysis in the neurovascular unit after tPA administration.In contrast to experimental findings, clinical data to support the tPA–MMP-9 hypothesis remains to be fully elucidated. Stroke patients with elevated plasma levels of MMP-9 have greater brain injury and poorer neurologic outcome,23 although the indirect confounds of stroke severity versus causality will need to be clarified. MMP-9 levels are increased in patients who receive tPA,24 and perhaps most importantly, those who suffer cerebral hemorrhage after tPA have higher plasma MMP-9 levels that those who do not.25 More broadly, MMPs have also been implicated in atherosclerosis and cardiovascular disease.26,27 Further studies are warranted to carefully assess the implications of MMP dysregulation in stroke patients.Targeting Neurovascular ProteolysisThe tPA–MMP-9 hypothesis may suggest new approaches for stroke therapy. In a rat model of focal stroke, co-treatment with tPA plus MMP inhibitors ameliorated reperfusion injury.28 Interferon-beta downregulates MMPs, suggesting another therapeutic combination.29 Alternatively, blocking neurotoxic properties of tPA with neuroserpin, neuronal serine protease inhibitor, increased the time-to-treatment window for thrombolysis in rat stroke models.30 Finally, there may be thrombolytic agents such as microplasmin31 or vampire bat salivary plasminogen activator32 that may not trigger MMP dysregulation or enhance excitotoxic neurodegeneration.Over a decade of monotherapies focused on only neurons have not yielded successful stroke treatments for humans. Expanding the focus to include other cells and matrix may provide a more comprehensive and realistic view of brain injury. Understanding how tPA relates to proteolytic dysregulation within the neurovascular unit may lead to novel ways of approaching stroke therapy.33,34 Recently, it was found that beta-amyloid upregulates MMP-2, MMP-9, and plasminogen activators in cerebral microvessels.35–37 Hence, it is possible that neurovascular proteolysis may also have broader implications for vascular dementia and neurodegeneration in general.The majority of data reviewed here were derived from cell culture systems and animal models of stroke, and the concepts and hypotheses discussed will have to be carefully validated in patients. Properly titrated use of tPA is clearly beneficial to reperfuse ischemic brain and rescue compromised tissue. Approaches that optimize tPA thrombolysis may lengthen the time-to-treatment windows and render reperfusion therapy even safer and more efficacious.The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.This work was supported in part by NIH grants P50-NS10828, R01-NS37074, R01-NS38731, and R01-NS40529.FootnotesCorrespondence to Eng H. Lo, Neuroprotection Research Laboratory, Harvard Medical School, MGH East 149-2401, Charlestown, MA 02129. E-mail [email protected] References 1 Report of the NINDS Stroke Progress Review Group 2002; 1-116. Available at www.ninds.gov/about_ninds/04_2002_stroke_PRG_report.htm.Google Scholar2 NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.CrossrefMedlineGoogle Scholar3 Hacke W, Brott T, Caplan L, Meier D, Fieschi C, von Kummer R, Donnan G, Heiss WD, Wahlgren NG, Spranger M, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology. 1999; 53: S3–S14.CrossrefMedlineGoogle Scholar4 Marler JR, Goldstein LB. Stroke: tPA and the clinic. Science. 2003; 301: 1677.Editorial.CrossrefMedlineGoogle Scholar5 Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke. 2003; 34: 1437–1442.LinkGoogle Scholar6 Tsirka SE, Rogove AD, Strickland S. Neuronal cell death and TPA. Nature. 1996; 384: 123–124.CrossrefMedlineGoogle Scholar7 Wang YF, Tsirka SE, Strickland S, Steig PE, Soriano SG, Lipton SA. TPA increases neuronal damage after focal cerebral ischemia in wild type and TPA-deficient mice. Nature Med. 1998; 4: 228–231.CrossrefMedlineGoogle Scholar8 Nicole O, Docagne F, Ali C, Margail I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Med. 2001; 7: 59–64.CrossrefMedlineGoogle Scholar9 Indyk JA, Chen ZL, Tsirka SE, Strickland S. Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury. Neuroscience. 2003; 116: 359–371.CrossrefMedlineGoogle Scholar10 Junge CE, Sugawara T, Mannaioni G, Alagarsamy S, Conn PJ, Brat DJ, Chan PH, Traynelis SF. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci U S A. 2003; 100: 13019–13024.CrossrefMedlineGoogle Scholar11 Yong VW, Power C, Forsyth P, Edwards DR. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001; 2: 502–511.CrossrefMedlineGoogle Scholar12 Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002; 39: 279–291.CrossrefMedlineGoogle Scholar13 Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001; 21: 7724–7732.CrossrefMedlineGoogle Scholar14 Lee SR, Tsuji K, Lee SR, Lo EH. Role of matrix metalloproteinase in delayed neuronal damage after transient global cerebral ischemia. J Neurosci. In press.Google Scholar15 Lo EH, Wang X, Cuzner ML. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J Neurosci Res. 2002; 69: 1–9.CrossrefMedlineGoogle Scholar16 Aoki T, Sumii T, Mori T, Wang X, Lo EH. Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke. 2002; 33: 2711–2717.LinkGoogle Scholar17 Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002; 33: 831–836.CrossrefMedlineGoogle Scholar18 Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, Lo EH. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003; 9: 1313–1317.CrossrefMedlineGoogle Scholar19 Siao CJ, Tsirka SE. Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J Neurosci. 2002; 22: 3352–3358.CrossrefMedlineGoogle Scholar20 Son H, Seuk Kim J, Mogg Kim J, Lee SH, Lee YS. Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons. Biochem Biophys Res Commun. 2002; 298: 262–268.CrossrefMedlineGoogle Scholar21 Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001; 108: 779–784.CrossrefMedlineGoogle Scholar22 Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor related protein. J Clin Invest. 2003; 112: 1533–1540.CrossrefMedlineGoogle Scholar23 Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, Davalos A. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke. 2003; 34: 40–46.LinkGoogle Scholar24 Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003; 34: 2165–2170.LinkGoogle Scholar25 Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003; 107: 598–603.LinkGoogle Scholar26 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002; 90: 251–262.LinkGoogle Scholar27 Lee RT, Libby P. Matrix metalloproteinases: not-so-innocent bystanders in heart failure. J Clin Invest. 2000; 106: 827–828.CrossrefMedlineGoogle Scholar28 Pfefferkon T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003; 34: 2025–2030.LinkGoogle Scholar29 Veldhius WB, Floris S, van der Meide PH, Vos IM, de Vries HE, Dijkstra CD, Bar PR, Nicolay K. Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood-brain barrier disruption. J Cereb Blood Flow Metab. 2003; 23: 1060–1069.CrossrefMedlineGoogle Scholar30 Zhang L, Zhang L, Yepes M, Jiang Q, Li Q, Arniego P, Coleman TA, Lawrence DA, Chopp M. Adjuvant treatment with neuroserpin increases the therapeutic window for tPA administration in a rat model of embolic stroke. Circulation. 2002; 106: 740–745.LinkGoogle Scholar31 Lapchak PA, Arujo DM, Pakola S, Song D, Wei J, Zivin JA. Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits. Stroke. 2002; 33: 2279–2284.LinkGoogle Scholar32 Liberatore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL. Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003; 34: 537–543.LinkGoogle Scholar33 del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003; 23: 879–894.CrossrefMedlineGoogle Scholar34 Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003; 4: 399–415.CrossrefMedlineGoogle Scholar35 Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, Hsu CY, Xu J. Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann Neurol. 2003; 54: 379–382.CrossrefMedlineGoogle Scholar36 Jung SS, Zhang W, van Nostrand WE. Pathogenic beta-amyloid induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells. J Neurochem. 2003; 85: 1208–1215.CrossrefMedlineGoogle Scholar37 Davis J, Wagner MR, Zhang W, Xu F, van Nostrand WE. Amyloid beta protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. J Biol Chem. 2003; 278: 19054–19061.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rosenberg G, Maki T, Arai K and Lo E (2022) Gliovascular Mechanisms and White Matter Injury in Vascular Cognitive Impairment and Dementia Stroke, 10.1016/B978-0-323-69424-7.00013-2, (153-160.e4), . Posada-Duque R, Cardona-Gómez G, Rao K, Britton G, Rocha Arrieta L, Garcia-Cairasco N, Lazarowski A, Palacios A, Espuny A and Maccioni R CDK5 Targeting as a Therapy for Recovering Neurovascular Unit Integrity in Alzheimer’s Disease, Journal of Alzheimer's Disease, 10.3233/JAD-200730, 82:s1, (S141-S161) Jiang Y, Liu N, Han J, Li Y, Spencer P, Vodovoz S, Ning M, Bix G, Katakam P, Dumont A and Wang X (2020) Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy, Translational Stroke Research, 10.1007/s12975-020-00872-3, 12:3, (416-427), Online publication date: 1-Jun-2021. Luo D, Chelales E, Beard M, Kasireddy N and Khismatullin D (2021) Drop-of-blood acoustic tweezing technique for integrative turbidimetric and elastometric measurement of blood coagulation, Analytical and Bioanalytical Chemistry, 10.1007/s00216-021-03278-8, 413:12, (3369-3379), Online publication date: 1-May-2021. Yang S and Liu R (2021) Four Decades of Ischemic Penumbra and Its Implication for Ischemic Stroke, Translational Stroke Research, 10.1007/s12975-021-00916-2, 12:6, (937-945), Online publication date: 1-Dec-2021. Wang L, Xiong X, Zhang L and Shen J (2021) Neurovascular Unit: A critical role in ischemic stroke, CNS Neuroscience & Therapeutics, 10.1111/cns.13561, 27:1, (7-16), Online publication date: 1-Jan-2021. Liu M, Li H, Zhang L, Xu Z, Song Y, Wang X, Chu R, Xiao Y, Sun M, Ma Y and Mi W (2021) Cottonseed Oil Alleviates Ischemic Stroke-Induced Oxidative Stress Injury Via Activating the Nrf2 Signaling Pathway, Molecular Neurobiology, 10.1007/s12035-020-02256-y, 58:6, (2494-2507), Online publication date: 1-Jun-2021. Zhang X, Gu Y, Xu W, Song Y, Zhang A, Zhang Z, Jiang S, Chang S, Ni G and Wang L (2020) Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway, Neural Plasticity, 10.1155/2020/8851089, 2020, (1-15), Online publication date: 11-Nov-2020. Liu M, Xu Z, Wang L, Zhang L, Liu Y, Cao J, Fu Q, Liu Y, Li H, Lou J, Hou W, Mi W and Ma Y (2020) Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte, Journal of Neuroinflammation, 10.1186/s12974-020-01946-7, 17:1, Online publication date: 1-Dec-2020. Ohtomo R and Arai K (2020) Recent updates on mechanisms of cell-cell interaction in oligodendrocyte regeneration after white matter injury, Neuroscience Letters, 10.1016/j.neulet.2019.134650, 715, (134650), Online publication date: 1-Jan-2020. Virdi J, Bhanot A, Jaggi A and Agarwal N (2020) Investigation on beneficial role of l -carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway , International Journal of Neuroscience, 10.1080/00207454.2020.1715393, 130:10, (983-998), Online publication date: 2-Oct-2020. Yoon B, Buch K, Lang M, Applewhite B, Li M, Mehan W, Leslie-Mazwi T and Rincon S (2020) Clinical and Neuroimaging Correlation in Patients with COVID-19, American Journal of Neuroradiology, 10.3174/ajnr.A6717, 41:10, (1791-1796), Online publication date: 1-Oct-2020. Zhang Y, Shi C, Chen Y, Wang W, Huang S, Han Z, Lin X, Lu F, Shen M and Scuderi G (2020) Retinal Structural and Microvascular Alterations in Different Acute Ischemic Stroke Subtypes, Journal of Ophthalmology, 10.1155/2020/8850309, 2020, (1-10), Online publication date: 9-Dec-2020. Nakamura Y, Park J and Hayakawa K (2020) Therapeutic use of extracellular mitochondria in CNS injury and disease, Experimental Neurology, 10.1016/j.expneurol.2019.113114, 324, (113114), Online publication date: 1-Feb-2020. Zhou R, Leng T, Yang T, Chen F, Hu W and Xiong Z (2019) β-Estradiol Protects Against Acidosis-Mediated and Ischemic Neuronal Injury by Promoting ASIC1a (Acid-Sensing Ion Channel 1a) Protein Degradation, Stroke, 50:10, (2902-2911), Online publication date: 1-Oct-2019. Zhang K, Tu M, Gao W, Cai X, Song F, Chen Z, Zhang Q, Wang J, Jin C, Shi J, Yang X, Zhu Y, Gu W, Hu B, Zheng Y, Zhang H and Tian M (2019) Hollow Prussian Blue Nanozymes Drive Neuroprotection against Ischemic Stroke via Attenuating Oxidative Stress, Counteracting Inflammation, and Suppressing Cell Apoptosis, Nano Letters, 10.1021/acs.nanolett.8b04729, 19:5, (2812-2823), Online publication date: 8-May-2019. Borlongan C (2019) Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet?, Stem Cells Translational Medicine, 10.1002/sctm.19-0076, 8:9, (983-988), Online publication date: 1-Sep-2019. Zhang Z, Zhao G, Liu L, He J, Darwazeh R, Liu H, Chen H, Zhou C, Guo Z and Sun X (2019) Bexarotene Exerts Protective Effects Through Modulation of the Cerebral Vascular Smooth Muscle Cell Phenotypic Transformation by Regulating PPARγ/FLAP/LTB 4 After Subarachnoid Hemorrhage in Rats , Cell Transplantation, 10.1177/0963689719842161, 28:9-10, (1161-1172), Online publication date: 1-Sep-2019. Chen Y, Zhang Y, Guo Z, Liu L, Gao F, Lv Y, Zhang M, Sun X, Obenaus A, Yang Y, Tang J, Feng H and Zhang J (2019) Neurovascular Network as Future Therapeutic Targets Cerebral Venous System in Acute and Chronic Brain Injuries, 10.1007/978-3-319-96053-1_1, (1-47), . Choi Y (2018) Role of Carbon Monoxide in Neurovascular Repair Processing, Biomolecules & Therapeutics, 10.4062/biomolther.2017.144, 26:2, (93-100), Online publication date: 1-Mar-2018. Katramados A, Hacein-Bey L and Varelas P (2018) What to Look for on Post-stroke Neuroimaging, Neuroimaging Clinics of North America, 10.1016/j.nic.2018.06.007, 28:4, (649-662), Online publication date: 1-Nov-2018. Noumbissi M, Galasso B and Stins M (2018) Brain vascular heterogeneity: implications for disease pathogenesis and design of in vitro blood–brain barrier models, Fluids and Barriers of the CNS, 10.1186/s12987-018-0097-2, 15:1, Online publication date: 1-Dec-2018. Chen S, Song H, Cui J, Shenker J, Chen Y, Sun G, Feng H and Gu Z (2018) Gelatinase-Mediated Impairment of Microvascular Beds in Cerebral Ischemia and Reperfusion Injury Cerebral Ischemic Reperfusion Injuries (CIRI), 10.1007/978-3-319-90194-7_1, (1-14), . Kim K, Lee S, Kim W, Seo J and Lee H (2017) How Can We Treat Cancer Disease Not Cancer Cells?, Cancer Research and Treatment, 10.4143/crt.2016.606, 49:1, (1-9), Online publication date: 15-Jan-2017. Brzica H, Abdullahi W, Ibbotson K and Ronaldson P (2017) Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke, Journal of Central Nervous System Disease, 10.1177/1179573517693802, 9, (117957351769380), Online publication date: 1-Jan-2017. Wesley U, Hatcher J, Ayvaci E, Klemp A and Dempsey R (2016) Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis, Molecular Neurobiology, 10.1007/s12035-016-0039-4, 54:7, (4973-4985), Online publication date: 1-Sep-2017. McInerney M, Short J and Nicolazzo J (2017) Neurovascular Alterations in Alzheimer’s Disease: Transporter Expression Profiles and CNS Drug Access, The AAPS Journal, 10.1208/s12248-017-0077-5, 19:4, (940-956), Online publication date: 1-Jul-2017. Okoreeh A, Bake S and Sohrabji F (2017) Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes, Glia, 10.1002/glia.23142, 65:7, (1043-1058), Online publication date: 1-Jul-2017. Gupta S, Sharma U, Jagannathan N and Gupta Y (2017) Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats, Experimental Neurology, 10.1016/j.expneurol.2016.10.014, 288, (25-37), Online publication date: 1-Feb-2017. Shindo A, Liang A, Maki T, Miyamoto N, Tomimoto H, Lo E and Arai K (2015) Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury, Journal of Cerebral Blood Flow & Metabolism, 10.1038/jcbfm.2015.80, 36:1, (187-198), Online publication date: 1-Jan-2016. Bake S, Okoreeh A, Alaniz R and Sohrabji F (2016) Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats, Endocrinology, 10.1210/en.2015-1840, 157:1, (61-69), Online publication date: 1-Jan-2016. Liang L, Yang J and Jin X (2016) Cocktail treatment, a promising strategy to treat acute cerebral ischemic stroke?, Medical Gas Research, 10.4103/2045-9912.179343, 6:1, (33), . Burchell S, Ho W, Tang J and Zhang J (2016) Neurovascular Repair After Stroke Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke, 10.1007/978-3-319-32337-4_17, (347-375), . Inoue K, Leng T, Yang T, Zeng Z, Ueki T and Xiong Z (2016) Role of serum- and glucocorticoid-inducible kinases in stroke, Journal of Neurochemistry, 10.1111/jnc.13650, 138:2, (354-361), Online publication date: 1-Jul-2016. Zhang J, Zou H, Zhang Q, Wang L, Lei J, Wang Y, Ouyang J, Zhang Y and Zhao H (2016) Effects of Xiaoshuan enteric-coated capsule on neurovascular functions assessed by quantitative multiparametric MRI in a rat model of permanent cerebral ischemia, BMC Complementary and Alternative Medicine, 10.1186/s12906-016-1184-z, 16:1, Online publication date: 1-Dec-2016. Shindo A, Maki T, Itoh K, Miyamoto N, Egawa N, Liang A, Noro T, Lok J, Lo E and Arai K (2016) Crosstalk Between Cerebral Endothelium and Oligodendrocyte After Stroke Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke, 10.1007/978-3-319-32337-4_8, (151-170), . Egawa N, Lok J and Arai K (2016) Mechanisms of cellular plasticity in cerebral perivascular region New Horizons in Neurovascular Coupling: A Bridge Between Brain Circulation and Neural Plasticity, 10.1016/bs.pbr.2016.03.005, (183-200), . Chelluboina B, Warhekar A, Dillard M, Klopfenstein J, Pinson D, Wang D and Veeravalli K (2015) Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage, Scientific Reports, 10.1038/srep09504, 5:1, Online publication date: 1-Aug-2015. Yang D and Kuan C (2014) Anti-tissue Plasminogen Activator (tPA) as an Effective Therapy of Neonatal Hypoxia-Ischemia with and without Inflammation, CNS Neuroscience & Therapeutics, 10.1111/cns.12365, 21:4, (367-373), Online publication date: 1-Apr-2015. Xu L, Guo R, Xie Y, Ma M, Ye R and Liu X (2015) Caveolae: molecular insights and therapeutic targets for stroke, Expert Opinion on Therapeutic Targets, 10.1517/14728222.2015.1009446, 19:5, (633-650), Online publication date: 4-May-2015. Lifshitz J (2015) Experimental CNS Trauma: A General Overview of Neurotraum