Research progress of neurovascular units involved in ischemic stroke

Abstract

Ischemic stroke is the most prevalent cerebrovascular disorder in the clinical setting. It results in associated neurological abnormalities due to a variety of factors, including disruption of cerebral arterial blood flow, hypoxia, and ischemic necrosis of local brain tissues. The neurovascular unit (NVU) is a dynamic structural complex that consists of neurons, glial cells, pericytes, vascular endothelial cells, and the extracellular matrix. Many cells work together to preserve the integrity of the central nervous system (CNS) under physiological conditions. However, following ischemic stroke, NVU homeostasis is disrupted along with the development of tissue ischemia and hypoxia, as well as impaired interactions between various components of the NVU. Collectively, the changes result in increased blood–brain barrier permeability, neuronal dysfunction, and functional destruction of nerve conduction bundles, ultimately leading to the clinical manifestation of neurological deficits including motor, cognitive, and speech impairments that hinder the rehabilitation process. In recent years, with continuously expanding research on ischemic cerebrovascular disease, the role of interconnections between different cells in the NVU in ischemic stroke has received increasing attention. To describe new concepts for the prevention and treatment of ischemic cerebrovascular illnesses, this article reviews the interplay between NVU in the pathogenesis of ischemic stroke.

Keywords

astrocyte / blood–brain barrier / ischemic stroke / neurovascular unit

References

[1] Zhao Y, Yang J, Li C, et al. Role of the neurovascular unit in the process of cerebral ischemic injury. Pharmacol Res. 2020; 160:105103.

[2] Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology. 2021; 97(20 Suppl 2):S6-S16.

[3] Leigh R, Knutsson L, Zhou J, van Zijl PC. Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke. J Cereb Blood Flow Metab. 2018; 38(9):1500-1516.

[4] Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta Neuropathol. 2019; 137(5):693-714.

[5] Sun M, Chen X, Yin YX, et al. Role of pericyte-derived SENP1 in neuronal injury after brain ischemia. CNS Neurosci Ther. 2020; 26(8):815-828.

[6] Yu X, Ji C, Shao A. Neurovascular unit dysfunction and neurodegenerative disorders. Front Neurosci. 2020; 14:334.

[7] Chen R, Xu X, Huang L, Zhong W, Cui L. The regulatory role of long noncoding RNAs in different brain cell types involved in ischemic stroke. Front Mol Neurosci. 2019; 12:61.

[8] Huang L, Nakamura Y, Lo EH, Hayakawa K. Astrocyte signaling in the neurovascular unit after central nervous system injury. Int J Mol Sci. 2019; 20(2):282.

[9] Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020; 17(1):69.

[10] Xiao M, Xiao ZJ, Yang B, Lan Z, Fang F. Blood-brain barrier: more contributor to disruption of central nervous system homeostasis than victim in neurological disorders. Front Neurosci. 2020; 14:764.

[11] Jiang X, Andjelkovic AV, Zhu L, et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018; 163-164:144-171.

[12] Lochhead JJ, Yang J, Ronaldson PT, Davis TP. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol. 2020; 11:914.

[13] Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019; 316(2):C135-C153.

[14] Bernardo-Castro S, Sousa JA, Brás A, et al. Pathophysiology of blood-brain barrier permeability throughout the different stages of ischemic stroke and its implication on hemorrhagic transformation and recovery. Front Neurol. 2020; 11:594672.

[15] Patabendige A, Singh A, Jenkins S, Sen J, Chen R. Astrocyte activation in neurovascular damage and repair following ischaemic stroke. Int J Mol Sci. 2021; 22(8):4280.

[16] Chen Y, Qin C, Huang J, et al. The role of astrocytes in oxidative stress of central nervous system: a mixed blessing. Cell Proliferation. 2020; 53(3):e12781.

[17] Kim E, Van Reet J, Kim HC, Kowsari K, Yoo SS. High incidence of intracerebral hemorrhaging associated with the application of low-intensity focused ultrasound following acute cerebrovascular injury by intracortical injection. Pharmaceutics. 2022; 14(10):2120.

[18] Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: a review. J Cereb Blood Flow Metab. 2016; 36(1):72-94.

[19] Zou J, Chen Z, Wei X, et al. Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units. Cell Death Dis. 2017; 8(6):e2854.

[20] Hashimoto Y, Greene C, Munnich A, Campbell M. The CLDN5 gene at the blood-brain barrier in health and disease. Fluids Barriers CNS. 2023; 20(1):22.

[21] Gong M, Jia J. Contribution of blood-brain barrier-related blood-borne factors for Alzheimer's disease vs. vascular dementia diagnosis: a pilot study. Front Neurosci. 2022; 16:949129.

[22] Yang G, Qian C, Wang N, et al. Tetramethylpyrazine protects against oxygen-glucose deprivation-induced brain microvascular endothelial cells injury via Rho/Rho-kinase signaling pathway. Cell Mol Neurobiol. 2017; 37(4):619-633.

[23] Reis PA, Castro-Faria-Neto HC. Systemic response to infection induces long-term cognitive decline: neuroinflammation and oxidative stress as therapeutical targets. Front Neurosci. 2022; 15:742158.

[24] Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019; 8(12):1605.

[25] Marino A, Baronio M, Buratti U, Mele E, Ciofani G. Porous optically transparent cellulose acetate scaffolds for biomimetic blood-brain barrier in vitro models. Front Bioeng Biotechnol. 2021; 9:630063.

[26] Gautam J, Miner JH, Yao Y. Loss of endothelial laminin α5 exacerbates hemorrhagic brain injury. Transl Stroke Res. 2019; 10(6):705-718.

[27] Kang M, Yao Y. Basement membrane changes in ischemic stroke. Stroke. 2020; 51(4):1344-1352.

[28] Thomsen MS, Routhe LJ, Moos T. The vascular basement membrane in the healthy and pathological brain. J Cereb Blood Flow Metab. 2017; 37(10):3300-3317.

[29] Rosenberg GA. Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin Sci. 2017; 131(6):425-437.

[30] Ren H, Wu Q, Sun Z, Fang M, Liu J, Luo J. Research progress and treatment of radiation enteritis and gut microbiota. Radiat Oncol J. 2023; 41(2):61-68.

[31] Rustenhoven J, Jansson D, Smyth LC, Dragunow M. Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci. 2017; 38(3):291-304.

[32] Wang H, Zhang R, Wu X, et al. The wnt signaling pathway in diabetic nephropathy. Front Cell Dev Biol. 2022; 9:701547.

[33] Underly RG, Levy M, Hartmann DA, Grant RI, Watson AN, Shih AY. Pericytes as inducers of rapid, matrix metalloproteinase-9-dependent capillary damage during ischemia. J Neurosci. 2017; 37(1):129-140.

[34] Cai W, Liu H, Zhao J, et al. Pericytes in brain injury and repair after ischemic stroke. Transl Stroke Res. 2017; 8(2):107-121.

[35] Su X, Huang L, Qu Y, Xiao D, Mu D. Pericytes in cerebrovascular diseases: an emerging therapeutic target. Front Cell Neurosci. 2019; 13:519.

[36] Wang F, Li R, Tu P, Chen J, Zeng K, Jiang Y. Total glycosides of Cistanche deserticola promote neurological function recovery by inducing neurovascular regeneration via Nrf-2/Keap-1 pathway in MCAO/R rats. Front Pharmacol. 2020; 11:236.

[37] Hur W, Kang BY, Kim SM, et al. Serine protease HtrA2/Omi deficiency impairs mitochondrial homeostasis and promotes hepatic fibrogenesis via activation of hepatic stellate cells. Cells. 2019; 8(10):1119.

[38] Nikolakopoulou AM, Montagne A, Kisler K, et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci. 2019; 22(7):1089-1098.

[39] Carlsson R, Özen I, Barbariga M, Gaceb A, Roth M, Paul G. STAT3 precedes HIF1α transcriptional responses to oxygen and oxygen and glucose deprivation in human brain pericytes. PLoS One. 2018; 13(3):e0194146.

[40] Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal cell death. Physiol Rev. 2018; 98(2):813-880.

[41] Zhang X, Zhang Y, Tang S, et al. Pien-Tze-Huang protects cerebral ischemic injury by inhibiting neuronal apoptosis in acute ischemic stroke rats. J Ethnopharmacol. 2018; 219:117-125.

[42] Arumugam TV, Baik SH, Balaganapathy P, Sobey CG, Mattson MP, Jo DG. Notch signaling and neuronal death in stroke. Prog Neurobiol. 2018; 165-167:103-116.

[43] Sanz P, Garcia-Gimeno MA. Reactive glia inflammatory signaling pathways and epilepsy. Int J Mol Sci. 2020; 21(11):4096.

[44] Lingam I, Robertson NJ. Magnesium as a neuroprotective agent: a review of its use in the fetus, term infant with neonatal encephalopathy, and the adult stroke patient. Dev Neurosci. 2018; 40(1):1-12.

[45] Zhang S, Wu M, Gu R, et al. Senegenin inhibits neuronal apoptosis after spinal cord contusion injury. Neural Regen Res. 2016; 11(4):657-663.

[46] Martínez-Coria H, Arrieta-Cruz I, Gutiérrez-Juárez R, López-Valdés HE. Anti-inflammatory effects of flavonoids in common neurological disorders associated with aging. Int J Mol Sci. 2023; 24(5):4297.

[47] Qu J, Zong HF, Shan Y, et al. Piezo1 suppression reduces demyelination after intracerebral hemorrhage. Neural Regen Res. 2023; 18(8):1750-1756.

[48] Mu JD, Ma LX, Zhang Z, et al. The factors affecting neurogenesis after stroke and the role of acupuncture. Front Neurol. 2023; 14:1082625.

[49] Wei Z, Xie Y, Wei M, et al. New insights in ferroptosis: potential therapeutic targets for the treatment of ischemic stroke. Front Pharmacol. 2022; 13:1020918.

[50] Michalski D, Keck AL, Grosche J, Martens H, Härtig W. Immunosignals of oligodendrocyte markers and myelin-associated proteins are critically affected after experimental stroke in wild-type and Alzheimer modeling mice of different ages. Front Cell Neurosci. 2018; 12:23.

[51] Bylicky MA, Mueller GP, Day RM. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid Med Cell Longevity. 2018; 2018:1-16.

[52] Poskanzer KE, Molofsky AV. Dynamism of an astrocyte in vivo: perspectives on identity and function. Annu Rev Physiol. 2018; 80:143-157.

[53] Bonetti NR, Diaz-Cañestro C, Liberale L, et al. Tumour necrosis factor-α inhibition improves stroke outcome in a mouse model of rheumatoid arthritis. Sci Rep. 2019; 9(1):2173.

[54] Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016; 19(2):182-189.

[55] Jurcau A, Simion A. Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: from pathophysiology to therapeutic strategies. Int J Mol Sci. 2021; 23(1):14.

[56] Escartin C, Galea E, Lakatos A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021; 24(3):312-325.

[57] Wang YF, Parpura V. Central role of maladapted astrocytic plasticity in ischemic brain edema formation. Front Cell Neurosci. 2016; 10:129.

[58] Sompol P, Norris CM. Ca2+, astrocyte activation and calcineurin/NFAT signaling in age-related neurodegenerative diseases. Front Aging Neurosci. 2018; 10:199.

[59] Escartin C, Guillemaud O, Carrillo-de Sauvage MA. Questions and (some) answers on reactive astrocytes. GLIA. 2019; 67(12):2221-2247.

[60] Yun SP, Kam TI, Panicker N, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med. 2018; 24(7):931-938.

[61] Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 541(7638):481-487.

[62] Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530(7589):177-183.

[63] Ponath G, Ramanan S, Mubarak M, et al. Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain. 2017; 140(2):399-413.

[64] Shehata MK, Ismail AA, Kamel MA. Combined donepezil with astaxanthin via nanostructured lipid carriers effective delivery to brain for Alzheimer's disease in rat model. Int J Nanomed. 2023; 18:4193-4227.

[65] Morizawa YM, Hirayama Y, Ohno N, et al. Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun. 2017; 8(1):28.

[66] Turnquist C, Horikawa I, Foran E, et al. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration. Cell Death Differ. 2016; 23(9):1515-1528.

[67] Renault-Mihara F, Mukaino M, Shinozaki M, et al. Regulation of RhoA by STAT3 coordinates glial scar formation. J Cell Biol. 2017; 216(8):2533-2550.

[68] Zhang Y, Xu D, Qi H, et al. Enriched environment promotes post-stroke neurogenesis through NF-κB-mediated secretion of IL-17A from astrocytes. Brain Res. 2018; 1687:20-31.

[69] Neal M, Luo J, Harischandra DS, et al. Prokineticin-2 promotes chemotaxis and alternative A2 reactivity of astrocytes. GLIA. 2018; 66(10):2137-2157.

[70] Horng S, Therattil A, Moyon S, et al. Astrocytic tight junctions control inflammatory CNS lesion pathogenesis. J Clin Invest. 2017; 127(8):3136-3151.

[71] Yamagata K. Lactate supply from astrocytes to neurons and its role in ischemic stroke-induced neurodegeneration. Neuroscience. 2022; 481:219-231.

[72] Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535(7613):551-555.

[73] Wang J, Sareddy GR, Lu Y, et al. Astrocyte-derived estrogen regulates reactive astrogliosis and is neuroprotective following ischemic brain injury. J Neurosci. 2020; 40(50):9751-9771.

[74] Lu Y, Sareddy GR, Wang J, et al. Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain. J Neurosci. 2020; 40(38):7355-7374.

[75] Guitart K, Loers G, Buck F, Bork U, Schachner M, Kleene R. Improvement of neuronal cell survival by astrocyte-derived exosomes under hypoxic and ischemic conditions depends on prion protein. GLIA. 2016; 64(6):896-910.

[76] Li Y, Fang J, Zhou Z, et al. Downregulation of lncRNA BACE1-AS improves dopamine-dependent oxidative stress in rats with Parkinson's disease by upregulating microRNA-34b-5p and downregulating BACE1. Cell Cycle. 2020; 19(10):1158-1171.

[77] Xu L, Cao H, Xie Y, et al. Exosome-shuttled miR-92b-3p from ischemic preconditioned astrocytes protects neurons against oxygen and glucose deprivation. Brain Res. 2019; 1717:66-73.

[78] Wu W, Liu J, Yang C, Xu Z, Huang J, Lin J. Astrocyte-derived exosome-transported microRNA-34c is neuroprotective against cerebral ischemia/reperfusion injury via TLR7 and the NF-κB/MAPK pathways. Brain Res Bull. 2020; 163:84-94.

[79] Verkman AS, Smith AJ, Phuan P, Tradtrantip L, Anderson MO. The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets. 2017; 21(12):1161-1170.

[80] Gleiser C, Wagner A, Fallier-Becker P, Wolburg H, Hirt B, Mack A. Aquaporin-4 in astroglial cells in the CNS and supporting cells of sensory organs—a comparative perspective. Int J Mol Sci. 2016; 17(9):1411.

[81] He T, Yang GY, Zhang Z. Crosstalk of astrocytes and other cells during ischemic stroke. Life. 2022; 12(6):910.

[82] Tan S, Shan Y, Lin Y, et al. Neutralization of interleukin-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A. FASEB J. 2019; 33(3):4376-4387.

[83] Shindo A, Maki T, Mandeville ET, et al. Astrocyte-derived pentraxin 3 supports blood–brain barrier integrity under acute phase of stroke. Stroke. 2016; 47(4):1094-1100.

[84] Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun. 2014; 5:3413.

[85] Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nature Neurosci. 2018; 21(10):1359-1369.

[86] Thion MS, Ginhoux F, Garel S. Microglia and early brain development: an intimate journey. Science. 2018; 362(6411):185-189.

[87] Frost JL, Schafer DP. Microglia: architects of the developing nervous system. Trends Cell Biol. 2016; 26(8):587-597.

[88] Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017; 35:441-468.

[89] Han D, Zhou Z, Liu J, Wang T, Yin J. Neuroprotective effects of isoflurane against lipopolysaccharide-induced neuroinflammation in BV2 microglial cells by regulating HMGB1/TLRs pathway. Folia Neuropathol. 2020; 58(1):57-69.

[90] Sapkota A, Gaire BP, Cho KS, et al. Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation. PLoS One. 2017; 12(2):e0171479.

[91] Gaire BP, Song MR, Choi JW. Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. J Neuroinflammation. 2018; 15(1):284.

[92] Esposito E, Hayakawa K, Ahn BJ, et al. Effects of ischemic post-conditioning on neuronal VEGF regulation and microglial polarization in a rat model of focal cerebral ischemia. J Neurochem. 2018; 146(2):160-172.

[93] Liu X, Liu J, Zhao S, et al. Interleukin-4 is essential for microglia/macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke. 2016; 47(2):498-504.

[94] Zhou D, Ji L, Chen Y. TSPO modulates IL-4-induced microglia/macrophage M2 polarization via PPAR-γ pathway. J Mol Neurosci. 2020; 70(4):542-549.

[95] Sampaio T, Savall A, Gutierrez MZ, Pinton S. Neurotrophic factors in Alzheimer's and Parkinson's diseases: implications for pathogenesis and therapy. Neural Regen Res. 2017; 12(4):549-557.

[96] Giera S, Luo R, Ying Y, et al. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. eLife. 2018; 7:e33385.

[97] Sato K, Shimizu H, Inoue T, Fujimura M, Endo H, Tominaga T. Temporal and spatial changes in cerebral blood flow during management for preventing delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: serial semiquantitative analysis. J Stroke Cerebrovasc Dis. 2017; 26(9):2027-2037.

[98] Li F, Ma Q, Zhao H, et al. L-3-n-Butylphthalide reduces ischemic stroke injury and increases M2 microglial polarization. Metab Brain Dis. 2018; 33(6):1995-2003.

[99] Zhang J, Han J, Zou J, Jiang C, Zhou C. Gualou Guizhi decoction improves glucose metabolism and alleviates microglia-associated inflammation after cerebral ischemia. Evid Based Complement Alternat Med. 2022; 2022:1-12.

[100] Zhou T, Huang Z, Sun X, et al. Microglia polarization with M1/M2 phenotype changes in rd1 mouse model of retinal degeneration. Front Neuroanat. 2017; 11:77.

[101] Perego C, Fumagalli S, Zanier ER, et al. Macrophages are essential for maintaining a M2 protective response early after ischemic brain injury. Neurobiol Dis. 2016; 96:284-293.

[102] Wang J, Xing H, Wan L, Jiang X, Wang C, Wu Y. Treatment targets for M2 microglia polarization in ischemic stroke. Biomed Pharmacother. 2018; 105:518-525.

[103] Choi YH, Laaker C, Hsu M, Cismaru P, Sandor M, Fabry Z. Molecular mechanisms of neuroimmune crosstalk in the pathogenesis of stroke. Int J Mol Sci. 2021; 22(17):9486.

[104] Wen RX, Shen H, Huang SX, et al. P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis. CNS Neurosci Ther. 2020; 26(4):416-429.

[105] Xu S, Lu J, Shao A, Zhang JH, Zhang J. Glial cells: role of the immune response in ischemic stroke. Front Immunol. 2020; 11:294.

[106] Cai W, Dai X, Chen J, et al. STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. JCI Insight. 2019; 4(20):e131355.

[107] Butler CA, Popescu AS, Kitchener EJA, Allendorf DH, Puigdellívol M, Brown GC. Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem. 2021; 158(3):621-639.

[108] Andoh M, Koyama R. Comparative review of microglia and monocytes in CNS phagocytosis. Cells. 2021; 10(10):2555.

[109] Sun H, He X, Tao X, et al. The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke. J Neuroinflammation. 2020; 17(1):171.

[110] Joy MT, Carmichael ST. Encouraging an excitable brain state: mechanisms of brain repair in stroke. Nat Rev Neurosci. 2021; 22(1):38-53.

RIGHTS & PERMISSIONS

2024 The Authors. Ibrain published by Affiliated Hospital of Zunyi Medical University and Wiley-VCH GmbH.