Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Maiko T Uemura, Takakuni Maki, Masafumi Ihara, Virginia M Y Lee, John Q Trojanowski, Maiko T Uemura, Takakuni Maki, Masafumi Ihara, Virginia M Y Lee, John Q Trojanowski

Abstract

Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.

Keywords: Alzheimer’s disease (AD); blood–brain barrier (BBB); mural cells; neurovascular coupling (NVC); pericytes; small vessel disease; stroke; vascular cognitive impairment and dementia.

Copyright © 2020 Uemura, Maki, Ihara, Lee and Trojanowski.

Figures

FIGURE 1
FIGURE 1
Brain vessels and mural cells. The pial arterioles branch from pial arteries which follow the outer rim of the brain via the meninges. The arterioles penetrate perpendicularly into the brain parenchyma (penetrating arteries) and further split into smaller arterioles. As their diameters and constituent cell types are changed, the vessels make a transition to capillaries. The capillary join to form venules that collect into pial venules and further into pial veins. In the small vessels, there are two types of mural cells separately located outside of endothelial layer: vascular smooth muscle cells (SMCs) and pericytes. SMCs are localized at the arteries, arterioles, venules and veins whereas pericytes are localized at the capillaries and post-capillary venules. The proximal branches coming off penetrating arterioles are sometimes called as pre-capillary arterioles. The subtypes of pericytes are differently called: ensheathing pericytes, transitional pericytes, pre-capillary pericytes, smooth muscle cell-pericyte hybrids, arteriole SMC (aaSMCs), or pre-capillary SMCs in a few branches from arterioles; capillary pericytes, mesh pericytes, thin-strand pericytes, helical pericytes, or mid-capillary pericytes in the middle part of capillary; mesh pericytes, stellate/stellate-like pericytes, or post-capillary pericytes in the post-capillary venules.
FIGURE 2
FIGURE 2
Constituents of the BBB in the capillary. In the BBB, tight junctions created by endothelial cells strictly regulate the movement of ions, molecules, and cells between the blood and the brain. The tight junctions are controlled by the cells surrounding the endothelium, including pericytes, astrocytes, perivascular OPCs, interneurons, perivascular macrophages, and microglia. Pericytes are localized on the abluminal surface of the endothelial layers and embedded in the basement membrane. Astrocytes extend polarized cellular processes that almost completely ensheath the vessel tubes.

References

    1. Abbott J. N., Pizzo M. E., Preston J. E., Janigro D., Thorne R. G. (2018). The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol. 135 387–407. 10.1007/s00401-018-1812-4
    1. Abbott N. J., Patabendige A. A., Dolman D. E., Yusof S. R., Begley D. J. (2010). Structure and function of the blood-brain barrier. Neurobiol. Dis. 37 13–25. 10.1016/j.nbd.2009.07.030
    1. Absinta M., Ha S. K., Nair G., Sati P., Luciano N. J., Palisoc M., et al. (2017). Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife 6:29738. 10.7554/eLife.29738
    1. Ahn J. H., Cho H., Kim J. H., Kim S. H., Ham J. S., Park I., et al. (2019). Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572 62–66. 10.1038/s41586-019-1419-5
    1. Akwii R. G., Sajib M. S., Zahra F. T., Mikelis C. M. (2019). Role of Angiopoietin-2 in vascular physiology and pathophysiology. Cells. 8:471. 10.3390/cells8050471
    1. Alarcon-Martinez L., Yilmaz-Ozcan S., Yemisci M., Schallek J., Kilic K., Can A., et al. (2018). Capillary pericytes express alpha-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. Elife 7:e34861. 10.7554/eLife.34861
    1. Alla B. S., Yulia K. K., Olga L. L., Alexander B. (2019). Pericyte biology in disease. Adv. Exp. Med. Biol. 1147 147–166. 10.1007/978-3-030-16908-4_7
    1. Allende M. L., Yamashita T., Proia R. L. (2003). G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102 3665–3667. 10.1182/blood-2003-02-0460
    1. Anderson M. A., Burda J. E., Ren Y., Ao Y., O’Shea T. M., Kawaguchi R., et al. (2016). Astrocyte scar formation aids central nervous system axon regeneration. Nature 532 195–200. 10.1038/nature17623
    1. Arango-Lievano M., Boussadia B., De Terdonck L. D. T., Gault C., Fontanaud P., Lafont C., et al. (2018). Topographic reorganization of cerebrovascular mural cells under seizure conditions. Cell Rep. 23 1045–1059. 10.1016/j.celrep.2018.03.110
    1. Armulik A., Abramsson A., Betsholtz C. (2005). Endothelial/Pericyte interactions. Circ. Res. 97 512–523. 10.1161/01.res.0000182903.16652.d7
    1. Armulik A., Genové G., Betsholtz C. (2011). Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21 193–215. 10.1016/j.devcel.2011.07.001
    1. Armulik A., Genové G., Mäe M., Nisancioglu M. H., Wallgard E., Niaudet C., et al. (2010). Pericytes regulate the blood-brain barrier. Nature 468 557–561. 10.1038/nature09522
    1. Asgari M., de Zelicourt D., Kurtcuoglu V. (2016). Glymphatic solute transport does not require bulk flow. Sci. Rep. 6:38635. 10.1038/srep38635
    1. Aspelund A., Antila S., Proulx S. T., Karlsen T. V., Karaman S., Detmar M., et al. (2015). A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212 991–999. 10.1084/jem.20142290
    1. Attwell D., Buchan A. M., Charpak S., Lauritzen M., Macvicar B. A., Newman E. A. (2010). Glial and neuronal control of brain blood flow. Nature 468 232–243. 10.1038/nature09613
    1. Attwell D., Mishra A., Hall C. N., O’Farrell F. M., Dalkara T. (2016). What is a pericyte? J. Cereb. Blood Flow Metab. 36 451–455. 10.1177/0271678x15610340
    1. Aydin F., Rosenblum W. I., Povlishock J. T. (1991). Myoendothelial junctions in human brain arterioles. Stroke 22 1592–1597. 10.1161/01.Str.22.12.1592
    1. Bai Y., Zhu X., Chao J., Zhang Y., Qian C., Li P., et al. (2015). Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke. PLoS One 10:e0124362. 10.1371/journal.pone.0124362
    1. Balabanov R., Beaumont T., Dore-Duffy P. (1999). Role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J. Neurosci. Res. 55 578–587. 10.1002/(sici)1097-4547(19990301)55:5<578::Aid-jnr5>;2-e
    1. Baloyannis S. J., Baloyannis I. S. (2012). The vascular factor in Alzheimer’s disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322 117–121. 10.1016/j.jns.2012.07.010
    1. Bandopadhyay R., Orte C., Lawrenson J. G., Reid A. R., Silva S. D., Allt G. (2001). Contractile proteins in pericytes at the blood-brain and blood-retinal barriers. J. Neurocytol. 30 35–44.
    1. Bell R. D., Winkler E. A., Sagare A. P., Singh I., LaRue B., Deane R., et al. (2010). Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68 409–427. 10.1016/j.neuron.2010.09.043
    1. Bell R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485 512–516. 10.1038/nature11087
    1. Berthiaume A.-A., Hartmann D. A., Majesky M. W., Bhat N. R., Shih A. Y. (2018). Pericyte structural remodeling in cerebrovascular health and homeostasis. Front. Aging Neurosci. 10:210. 10.3389/fnagi.2018.00210
    1. Bevan J. A., Dodge J., Walters C. L., Wellman T., Bevan R. D. (1999). As human pial arteries (internal diameter 200–1000 μm) get smaller, their wall thickness and capacity to develop tension relative to their diameter increase. Life Sci. 65 1153–1161. 10.1016/s0024-3205(99)00349-5
    1. Blocki A., Beyer S., Jung F., Raghunath M. (2018). The controversial origin of pericytes during angiogenesis – implications for cell-based therapeutic angiogenesis and cell-based therapies. Clin. Hemorheol. Microcirc. 69 215–232. 10.3233/ch-189132
    1. Boado R. J., Pardridge W. M. (1994). Differential expression of α−actin mRNA and immunoreactive protein in brain microvascular pericytes and smooth muscle cells. J. Neurosci. 39 430–435.
    1. Bondjers C., He L., Takemoto M., Norlin J., Asker N., Hellstrom M., et al. (2006). Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 20 1703–1705. 10.1096/fj.05-4944fje
    1. Bonkowski D., Katyshev V., Balabanov R. D., Borisov A., Dore-Duffy P. (2011). The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS 8:8. 10.1186/2045-8118-8-8
    1. Bosetti F., Galis Z. S., Bynoe M. S., Charette M., Cipolla M. J., Del Zoppo G. J., et al. (2016). Small blood vessels: big health problems?” Scientific recommendations of the national institutes of health workshop. J. Am. Heart Assoc. 5:e004389. 10.1161/jaha.116.004389
    1. Brown L. S., Foster C. G., Courtney J.-M., King N. E., Howells D. W., Sutherland B. A. (2019). Pericytes and neurovascular function in the healthy and diseased brain. Front. Cell. Neurosci. 13:282. 10.3389/fncel.2019.00282
    1. Cai C., Fordsmann J. C., Jensen S. H., Gesslein B., Lønstrup M., Hald B. O., et al. (2018). Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proc. Natl. Acad. Sci. 115 E5796–E5804. 10.1073/pnas.1707702115
    1. Carare R. O., Bernardes-Silva M., Newman T. A., Page A. M., Nicoll J. A., Perry V. H., et al. (2008). Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol. Appl. Neurobiol. 34 131–144. 10.1111/j.1365-2990.2007.00926.x
    1. Carare R. O., Hawkes C. A., Weller R. O. (2014). Afferent and efferent immunological pathways of the brain. Anatomy, function and failure. Brain Behav. Immun. 36 9–14. 10.1016/j.bbi.2013.10.012
    1. Cardona A. E., Pioro E. P., Sasse M. E., Kostenko V., Cardona S. M., Dijkstra I. M., et al. (2006). Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9 917–924. 10.1038/nn1715
    1. Cheng J., Korte N., Nortley R., Sethi H., Tang Y., Attwell D. (2018). Targeting pericytes for therapeutic approaches to neurological disorders. Acta Neuropathol. 136 507–523. 10.1007/s00401-018-1893-0
    1. Cheng Y., Wang Y. J. (2020). Meningeal lymphatic vessels: a drain of the brain involved in neurodegeneration? Neurosci. Bull. 10.1007/s12264-019-00456-8 [Epub ahead of print].
    1. Choe Y., Huynh T., Pleasure S. J. (2014). Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor β family proteins during corticogenesis. J. Neurosci. 34 14973–14983. 10.1523/JNEUROSCI.1156-14.2014
    1. Clark E. R., Clart E. L. (1940). Microscopic observations on the extra-endothelial cells of living mammalian blood vessels. Am. J. Anat. 66 39–49.
    1. Coatti G. C., Cavacana N., Zatz M. (2019). Pericyte biology in disease. Adv. Exp. Med. Biol. 1147 137–146. 10.1007/978-3-030-16908-4_6
    1. Craggs L., Yamamoto Y., Deramecourt V., Kalaria R. N. (2014). Microvascular pathology and morphometrics of sporadic and hereditary small vessel diseases of the brain. Brain Pathol. 24 495–509. 10.1111/bpa.12177
    1. Cullen M., Elzarrad M. K., Seaman S., Zudaire E., Stevens J., Yang M. Y., et al. (2011). GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl. Acad. Sci. U.S.A. 108 5759–5764. 10.1073/pnas.1017192108
    1. Dalkara T. (2019). Pericytes: a novel target to improve success of recanalization therapies. Stroke 50 2985–2991. 10.1161/strokeaha.118.023590
    1. Dalkara T., Alarcon-Martinez L. (2015). Cerebral microvascular pericytes and neurogliovascular signaling in health and disease. Brain Res. 1623 3–17. 10.1016/j.brainres.2015.03.047
    1. Dalkara T., Arsava E. (2012). Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis? J. Cereb. Blood Flow Metab. 32 2091–2099. 10.1038/jcbfm.2012.139
    1. Damisah E. C., Hill R. A., Tong L., Murray K. N., Grutzendler J. (2017). A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging. Nat. Neurosci. 20 1023–1032. 10.1038/nn.4564
    1. Daneman R., Prat A. (2015). The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 7:a020412. 10.1101/cshperspect.a020412
    1. Daneman R., Zhou L., Kebede A. A., Barres B. A. (2010). Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468 562–566. 10.1038/nature09513
    1. Darland D. C., Massingham L. J., Smith S. R., Piek E., Saint-Geniez M., D’Amore P. A. (2003). Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev. Biol. 264 275–288. 10.1016/j.ydbio.2003.08.015
    1. Davalos D., Ryu J., Merlini M., Baeten K. M., Moan N., Petersen M. A., et al. (2012). Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat. Commun. 3:1227. 10.1038/ncomms2230
    1. De La Fuente A. G., Lange S., Silva M. E., Gonzalez G. A., Tempfer H., van Wijngaarden P., et al. (2017). Pericytes stimulate oligodendrocyte progenitor cell differentiation during CNS remyelination. Cell Rep. 20 1755–1764. 10.1016/j.celrep.2017.08.007
    1. Deane R., Du Yan S., Submamaryan R. K., LaRue B., Jovanovic S., Hogg E., et al. (2003). RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 9 907–913. 10.1038/nm890
    1. Deane R., Singh I., Sagare A. P., Bell R. D., Ross N. T., LaRue B., et al. (2012). A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin. Invest. 122 1377–1392. 10.1172/jci58642
    1. Deguchi K., Liu N., Liu W., Omote Y., Kono S., Yunoki T., et al. (2014). Pericyte protection by edaravone after tissue plasminogen activator treatment in rat cerebral ischemia. J. Neurosci. Res. 92 1509–1519. 10.1002/jnr.23420
    1. Dias D., Kim H., Holl D., Solnestam B., Lundeberg J., Carlén M., et al. (2018). Reducing pericyte-derived scarring promotes recovery after spinal cord injury. Cell 173 153–165.e22. 10.1016/j.cell.2018.02.004
    1. Diaz-Flores L., Gutierrez R., Madrid J. F., Varela H., Valladares F., Acosta E., et al. (2009). Pericytes, morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24 909–969. 10.14670/HH-24.909
    1. Ding X., Gu R., Zhang M., Ren H., Shu Q., Xu G., et al. (2018). Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs. BMC Ophthalmol. 18:249. 10.1186/s12886-018-0886-z
    1. Dore-Duffy P., Katychev A., Wang X., Buren E. (2006). CNS microvascular pericytes exhibit multipotential stem cell activity. J. Cereb. Blood Flow Metab. 26 613–624. 10.1038/sj.jcbfm.9600272
    1. Duan L., Zhang X.-D., Miao W.-Y., Sun Y.-J., Xiong G., Wu Q., et al. (2018). PDGFRβ cells rapidly relay inflammatory signal from the circulatory system to neurons via chemokine CCL2. Neuron. 100 183–200.e8. 10.1016/j.neuron.2018.08.030
    1. Dudvarski Stankovic N., Teodorczyk M., Ploen R., Zipp F., Schmidt M. H. H. (2016). Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol. 131 347–363. 10.1007/s00401-015-1524-y
    1. Durham J. T., Surks H. K., Dulmovits B. M., Herman I. M. (2014). Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics. Am. J. Physiol. Cell Physiol. 307 C878–C892. 10.1152/ajpcell.00185.2014
    1. Eberth C. G. (1871). Handbuch der Lehre von der Gewegen des Menschen und der Tiere, Vol. 1 Leipzig: Engelmann.
    1. Eilken H. M., Diéguez-Hurtado R., Schmidt I., Nakayama M., Jeong H.-W., Arf H., et al. (2017). Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. Nat. Commun. 8:1574. 10.1038/s41467-017-01738-3
    1. El-Bouri W. K., Payne S. J. (2016). A statistical model of the penetrating arterioles and venules in the human cerebral cortex. Microcirculation 23 580–590. 10.1111/micc.12318
    1. Engelhardt B., Carare R. O., Bechmann I., Flugel A., Laman J. D., Weller R. O. (2016). Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132 317–338. 10.1007/s00401-016-1606-5
    1. Engelhardt B., Vajkoczy P., Weller R. O. (2017). The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18 123–131. 10.1038/ni.3666
    1. Erdener Ş. E., Dalkara T. (2019). Small vessels are a big problem in neurodegeneration and neuroprotection. Front. Neurol. 10:889. 10.3389/fneur.2019.00889
    1. Faal T., Phan D., Davtyan H., Scarfone V. M., Varady E., Blurton-Jones M., et al. (2019). Induction of mesoderm and neural crest-derived pericytes from human pluripotent stem cells to study blood-brain barrier interactions. Stem Cell Rep. 12 451–460. 10.1016/j.stemcr.2019.01.005
    1. Fabriek B. O., Haastert E. S., Galea I., Polfliet M., Döpp E. D., Heuvel M. M., et al. (2005). CD163−positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51 297–305. 10.1002/glia.20208
    1. Faraco G., Park L., Anrather J., Iadecola C. (2017). Brain perivascular macrophages: characterization and functional roles in health and disease. J. Mol. Med. 95 1143–1152. 10.1007/s00109-017-1573-x
    1. Farkas E., Luiten P. G. (2001). Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog. Neurobiol. 64 575–611. 10.1016/s0301-0082(00)00068-x
    1. Fernández-Klett F., Offenhauser N., Dirnagl U., Priller J., Lindauer U. (2010). Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc. Natl. Acad. Sci. U.S.A. 107 22290–22295. 10.1073/pnas.1011321108
    1. Fernández-Klett F., Potas J. R., Hilpert D., Blazej K., Radke J., Huck J., et al. (2013). Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J. Cereb. Blood Flow Metab. 33 428–439. 10.1038/jcbfm.2012.187
    1. Franco M., Roswall P., Cortez E., Hanahan D., Pietras K. (2011). Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118 2906–2917. 10.1182/blood-2011-01-331694
    1. Fu A. K., Hung K. W., Yuen M. Y., Zhou X., Mak D. S., Chan I. C., et al. (2016). IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proc. Natl. Acad. Sci. U.S.A. 113 E2705–E2713. 10.1073/pnas.1604032113
    1. Fullstone G., Nyberg S., Tian X., Battaglia G. (2016). From the blood to the central nervous system: a Nanoparticle’s journey through the blood-brain barrier by transcytosis. Int. Rev. Neurobiol. 130 41–72. 10.1016/bs.irn.2016.06.001
    1. Gaengel K., Genové G., Armulik A., Betsholtz C. (2009). Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29 630–638. 10.1161/atvbaha.107.161521
    1. Gaudin A., Yemisci M., Eroglu H., Lepetre-Mouelhi S., Turkoglu O. F., Donmez-Demir B., et al. (2014). Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury. Nat. Nanotechnol. 9 1054–1062. 10.1038/nnano.2014.274
    1. Gautam J., Yao Y. (2018). Roles of pericytes in stroke pathogenesis. Cell Transplant. 27 1798–1808. 10.1177/0963689718768455
    1. Geevarghese A., Herman I. M. (2014). Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies. Transl. Res. 163 296–306. 10.1016/j.trsl.2014.01.011
    1. Geraldes P., Hiraoka-Yamamoto J., Matsumoto M., Clermont A., Leitges M., Marette A., et al. (2009). Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15 1298–1306. 10.1038/nm.2052
    1. Geranmayeh M., Rahbarghazi R., Farhoudi M. (2019). Targeting pericytes for neurovascular regeneration. Cell Commun. Signal. 17:26. 10.1186/s12964-019-0340-8
    1. Ghosh M., Balbi M., Hellal F., Dichgans M., Lindauer U., Plesnila N. (2015). Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78 887–900. 10.1002/ana.24512
    1. Goldmann T., Wieghofer P., Jordão M., Prutek F., Hagemeyer N., Frenzel K., et al. (2016). Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17 797–805. 10.1038/ni.3423
    1. Göritz C., Dias D. O., Tomilin N., Barbacid M., Shupliakov O., Frisén J. (2011). A pericyte origin of spinal cord scar tissue. Science 333 238–242. 10.1126/science.1203165
    1. Gould I. G., Tsai P., Kleinfeld D., Linninger A. (2016). The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J. Cereb. Blood Flow Metab. 37 52–68. 10.1177/0271678X16671146
    1. Grant R. I., Hartmann D. A., Underly R. G., Berthiaume A.-A., Bhat N. R., Shih A. Y. (2019). Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex. J. Cereb. Blood Flow Metab. 39 411–425. 10.1177/0271678x17732229
    1. Grubb S., Cai C., Hald B. O., Khennouf L., Murmu R. P., Jensen A. G. K., et al. (2020). Precapillary sphincters maintain perfusion in the cerebral cortex. Nat. Commun. 11:395. 10.1038/s41467-020-14330-z
    1. Guadagno E., Moukhles H. (2004). Laminin−induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water−permeable channel, AQP4, via a dystroglycan−containing complex in astrocytes. Glia 47 138–149. 10.1002/glia.20039
    1. Guijarro-Muñoz I., Compte M., Álvarez-Cienfuegos A., Álvarez-Vallina L., Sanz L. (2014). Lipopolysaccharide activates toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway and proinflammatoryresponse in human pericytes. J. Biol. Chem. 4 2457–2468.
    1. Guimaraes-Camboa N., Cattaneo P., Sun Y., Moore-Morris T., Gu Y., Dalton N. D., et al. (2017). Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20 345–359.e5. 10.1016/j.stem.2016.12.006
    1. Gursoy-Ozdemir Y., Yemisci M., Dalkara T. (2012). Microvascular protection is essential for successful neuroprotection in stroke. J. Neurochem. 123(Suppl. 2) 2–11. 10.1111/j.1471-4159.2012.07938.x
    1. Gyoneva S., Davalos D., Biswas D., Swanger S. A., Garnier-Amblard E., Loth F., et al. (2014). Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62 1345–1360. 10.1002/glia.22686
    1. Hall C. N., Reynell C., Gesslein B., Hamilton N. B., Mishra A., Sutherland B. A., et al. (2014). Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508 55–60. 10.1038/nature13165
    1. Halliday M. R., Rege S. V., Ma Q., Zhao Z., Miller C. A., Winkler E. A., et al. (2016). Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J. Cereb. Blood Flow Metab. 36 216–227. 10.1038/jcbfm.2015.44
    1. Hamilton N. B., Attwell D., Hall C. N. (2010). Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenergetics. 2:5. 10.3389/fnene.2010.00005
    1. Harnarine-Singh D., Geddes G., Hyde J. B. (1972). Sizes and numbers of arteries and veins in normal human neopallium. J. Anat. 111 171–179.
    1. Hartmann D. A., Underly R. G., Grant R. I., Watson A. N., Lindner V., Shih A. Y. (2015). Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics 2:041402. 10.1117/1.nph.2.4.041402
    1. Hashitani H., Lang R. J. (2016). Spontaneous activity in the microvasculature of visceral organs: role of pericytes and voltage−dependent Ca2+ channels. J. Physiol. 594 555–565. 10.1113/jp271438
    1. Hatterer E., Davoust N., Didier-Bazes M., Vuaillat C., Malcus C., Belin M. F., et al. (2006). How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107 806–812. 10.1182/blood-2005-01-0154
    1. He L., Vanlandewijck M., Raschperger E., Mäe M., Jung B., Lebouvier T., et al. (2016). Analysis of the brain mural cell transcriptome. Sci. Rep. 6:35108. 10.1038/srep35108
    1. He M., Dong H., Huang Y., Lu S., Zhang S., Qian Y., et al. (2016). Astrocyte-derived CCL2 is associated with M1 activation and recruitment of cultured microglial cells. Cell. Physiol. Biochem. 38 859–870. 10.1159/000443040
    1. Hellström M., Gerhardt H., Kalén M., Li X., Eriksson U., Wolburg H., et al. (2001). Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153 543–554. 10.1083/jcb.153.3.543
    1. Herland A., van der Meer A. D., FitzGerald E. A., Park T.-E., Sleeboom J. J. F., Ingber D. E. (2016). Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood-brain barrier on a chip. PLoS One 11:e0150360. 10.1371/journal.pone.0150360
    1. Hesp Z. C., Yoseph R. Y., Suzuki R., Jukkola P., Wilson C., Nishiyama A., et al. (2018). Proliferating NG2 cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice. J. Neurosci. 38 1366–1382. 10.1523/jneurosci.3953-16.2017
    1. Hill R. A., Tong L., Yuan P., Murikinati S., Gupta S., Grutzendler J. (2015). Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87 95–110. 10.1016/j.neuron.2015.06.001
    1. Hladky S. B., Barrand M. A. (2014). Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11:26. 10.1186/2045-8118-11-26
    1. Hladky S. B., Barrand M. A. (2019). Is solute movement within the extracellular spaces of brain gray matter brought about primarily by diffusion or flow? A commentary on “Analysis of convective and diffusive transport in the brain interstitium” Fluids and Barriers of the CNS (2019) 16:6 by L. Ray, J.J. Iliff and J.J. Heys. Fluids Barriers CNS 16:24. 10.1186/s12987-019-0141-x
    1. Holter K. E., Kehlet B., Devor A., Sejnowski T. J., Dale A. M., Omholt S. W., et al. (2017). Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. Proc. Natl. Acad. Sci. U.S.A. 114 9894–9899. 10.1073/pnas.1706942114
    1. Hughes S., Chan-Ling T. (2004). Characterization of smooth muscle cell and pericyte differentiation in the rat retina in vivo. Invest. Ophthalmol. Vis. Sci. 45 2795–2806. 10.1167/iovs.03-1312
    1. Hunter J. M., Kwan J., Malek-Ahmadi M., Maarouf C. L., Kokjohn T. A., Belden C., et al. (2012). Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer’s disease. PLoS One. 7:e36893. 10.1371/journal.pone.0036893
    1. Iadecola C. (2004). Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5 347–360. 10.1038/nrn1387
    1. Iadecola C. (2017). The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96 17–42. 10.1016/j.neuron.2017.07.030
    1. Ihara M., Yamamoto Y. (2016). Emerging evidence for pathogenesis of sporadic cerebral small vessel disease. Stroke 47 554–560. 10.1161/STROKEAHA.115.009627
    1. Iliff J. J., Wang M., Liao Y., Plogg B. A., Peng W., Gundersen G. A., et al. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4:147ra111. 10.1126/scitranslmed.3003748
    1. Iris A., Christian H., Nikolaos S., Ajna B., Truman R. B., Yaakov S. (2007). Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer’s disease. J. Cereb. Blood Flow Metab. 28 725–736. 10.1038/sj.jcbfm.9600570
    1. Itoh Y., Suzuki N. (2012). Control of brain capillary blood flow. J. Cereb. Blood Flow Metab. 32 1167–1176. 10.1038/jcbfm.2012.5
    1. Iturria-Medina Y., Sotero R. C., Toussaint P. J., Mateos-Perez J. M., Evans A. C. (2016). Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7:11934. 10.1038/ncomms11934
    1. Jessen N., Munk A., Lundgaard I., Nedergaard M., Nedergaard N. (2015). The glymphatic system: a beginner’s guide. Neurochem. Res. 40 2583–2599. 10.1007/s11064-015-1581-6
    1. Jian H., Shi-Ting L., Qi L., Qing-Gang P., Fei G., Mei-Xiu D. (2003). Vascular endothelial growth factor expression and angiogenesis induced by chronic cerebral hypoperfusion in rat brain. Neurosurgery 53 963–972. 10.1227/01.neu.0000083594.10117.7a
    1. Jin B. J., Smith A. J., Verkman A. S. (2016). Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J. Gen. Physiol. 148 489–501. 10.1085/jgp.201611684
    1. Joyce E. R. (2005). Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med. 9 267–285. 10.1111/j.1582-4934.2005.tb00355.x
    1. Khennouf L., Gesslein B., Brazhe A., Octeau J. C., Kutuzov N., Khakh B. S., et al. (2018). Active role of capillary pericytes during stimulation-induced activity and spreading depolarization. Brain 141 2032–2046. 10.1093/brain/awy143
    1. Kida S., Pantazis A., Weller R. O. (1993). CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19 480–488. 10.1111/j.1365-2990.1993.tb00476.x
    1. Kinney J. W., Bemiller S. M., Murtishaw A. S., Leisgang A. M., Salazar A. M., Lamb B. T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. Transl. Res. Clin. Interv. 4 575–590. 10.1016/j.trci.2018.06.014
    1. Kishida N., Maki T., Takagi Y., Yasuda K., Kinoshita H., Ayaki T., et al. (2019). Role of perivascular oligodendrocyte precursor cells in angiogenesis after brain ischemia. J. Am. Heart Assoc. 8:e011824. 10.1161/JAHA.118.011824
    1. Kisler K., Nelson A. R., Montagne A., Zlokovic B. V. (2017a). Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18 419–434. 10.1038/nrn.2017.48
    1. Kisler K., Nelson A. R., Rege S. V., Ramanathan A., Wang Y., Ahuja A., et al. (2017b). Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20 406–416. 10.1038/nn.4489
    1. Kisler K., Nikolakopoulou A. M., Sweeney M. D., Lazic D., Zhao Z., Zlokovic B. V. (2020). Acute ablation of cortical pericytes leads to rapid neurovascular uncoupling. Front. Cell. Neurosci. 14:27. 10.3389/fncel.2020.00027
    1. Kitaguchi H., Ihara M., Saiki H., Takahashi R., Tomimoto H. (2007). Capillary beds are decreased in Alzheimer’s disease, but not in Binswanger’s disease. Neurosci. Lett. 417 128–131. 10.1016/j.neulet.2007.02.021
    1. Kitaguchi H., Tomimoto H., Ihara M., Shibata M., Uemura K., Kalaria R. N., et al. (2009). Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain Res. 1294 202–210. 10.1016/j.brainres.2009.07.078
    1. Kloner R. A., King K. S., Harrington M. G. (2018). No-reflow phenomenon in the heart and brain. Am. J. Physiol. Heart Circ. Physiol. 315 H550–H562. 10.1152/ajpheart.00183.2018
    1. Kokovay E., Li L., Cunningham L. A. (2006). Angiogenic recruitment of pericytes from bone marrow after stroke. J. Cereb. Blood Flow Metab. 26 545–555. 10.1038/sj.jcbfm.9600214
    1. Kovac A., Erickson M. A., Banks W. A. (2011). Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide. J. Neuroinflamm. 8:139. 10.1186/1742-2094-8-139
    1. Krueger M., Bechmann I. (2010). CNS pericytes: concepts, misconceptions, and a way out. Glia 58 1–10. 10.1002/glia.20898
    1. Kuhnert F., Mancuso M. R., Shamloo A., Wang H. T., Choksi V., Florek M., et al. (2010). Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330 985–989. 10.1126/science.1196554
    1. Kunz J., Krause D., Marian K., Dermietzel R. (1994). The 140-kDa protein of blood-brain barrier-associated pericytes is identical to aminopeptidase. N. J. Neurochem. 62 2375–2386. 10.1046/j.1471-4159.1994.62062375.x
    1. Landau J., Davis E. (1957). Capillary thinning and high capillary blood-pressure in hypertension. Lancet 269 1327–1330. 10.1016/s0140-6736(57)91847-0
    1. Lapenna A., Palma M., Lewis C. E. (2018). Perivascular macrophages in health and disease. Nat. Rev. Immunol. 18 689–702. 10.1038/s41577-018-0056-9
    1. Leijenaar J. F., van Maurik I. S., Kuijer J. P. A., van der Flier W. M., Scheltens P., Barkhof F., et al. (2017). Lower cerebral blood flow in subjects with Alzheimer’s dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging. Alzheimers Dement. Transl. Res. Clin. Interv. 9 76–83. 10.1016/j.dadm.2017.10.001
    1. Lendahl U., Nilsson P., Betsholtz C. (2019). Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes. EMBO Rep. 20:e48070. 10.15252/embr.201948070
    1. Li F., Lan Y., Wang Y., Wang J., Yang G., Meng F., et al. (2011). Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with notch. Dev. Cell 20 291–302. 10.1016/j.devcel.2011.01.011
    1. Lindahl P., Johansson B. R., Levéen P., Betsholtz C. (1997). Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277 242–245. 10.1126/science.277.5323.242
    1. Liu C., Ge H.-M., Liu B.-H., Dong R., Shan K., Chen X., et al. (2019). Targeting pericyte–endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction. Proc. Natl. Acad. Sci. U.S.A. 116 7455–7464. 10.1073/pnas.1814874116
    1. Liu H., Zhang W., Kennard S., Caldwell R. B., Lilly B. (2010). Notch3 is critical for proper angiogenesis and mural cell investment. Circ. Res. 107 860–870. 10.1161/circresaha.110.218271
    1. Liu Q., Radwanski R., Babadjouni R., Patel A., Hodis D. M., Baumbacher P., et al. (2019). Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood–brain barrier permeability in the corpus callosum. J. Cereb. Blood Flow Metab. 39 240–250. 10.1177/0271678x17743670
    1. Liu S., Agalliu D., Yu C., Fisher M. (2012). The role of pericytes in blood-brain barrier function and stroke. Curr. Pharm. Des. 18 3653–3662. 10.2174/138161212802002706
    1. Liu Y., Wada R., Yamashita T., Mi Y., Deng C. X., Hobson J. P., et al. (2000). Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106 951–961. 10.1172/jci10905
    1. Louveau A., Smirnov I., Keyes T. J., Eccles J. D., Rouhani S. J., Peske J. D., et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature 523 337–341. 10.1038/nature14432
    1. Luissint A.-C., Artus C., Glacial F., Ganeshamoorthy K., Couraud P.-O. (2012). Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS 9:23. 10.1186/2045-8118-9-23
    1. Ma Q., Zhao Z., Sagare A. P., Wu Y., Wang M., Owens N., et al. (2018). Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol. Neurodegener. 13:57. 10.1186/s13024-018-0286-0
    1. Maki T. (2017). Novel roles of oligodendrocyte precursor cells in the developing and damaged brain. Clin. Exp. Neuroimmunol. 8 33–42. 10.1111/cen3.12358
    1. Maki T., Choi Y. K., Miyamoto N., Shindo A., Liang A. C., Ahn B. J., et al. (2018). A-kinase anchor protein 12 is required for oligodendrocyte differentiation in adult white matter. Stem Cells 36 751–760. 10.1002/stem.2771
    1. Maki T., Maeda M., Uemura M., Lo E. K., Terasaki Y., Liang A. C., et al. (2015). Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. Neurosci. Lett. 597 164–169. 10.1016/j.neulet.2015.04.047
    1. Makihara N., Arimura K., Ago T., Tachibana M., Nishimura A., Nakamura K., et al. (2015). Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke. Exp. Neurol. 264 127–134. 10.1016/j.expneurol.2014.12.007
    1. Marín-Padilla M. (2012). The human brain intracerebral microvascular system: development and structure. Front. Neuroanat. 6:38. 10.3389/fnana.2012.00038
    1. Mastorakos P., McGavern D. (2019). The anatomy and immunology of vasculature in the central nervous system. Sci. Immunol. 4:eaav0492. 10.1126/sciimmunol.aav0492
    1. Matsumoto J., Dohgu S., Takata F., Machida T., Hatip F. F., Hatip-Al-Khatib I., et al. (2018). TNF-α-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IκB-NFκB and JAK-STAT3 pathways. Brain Res. 1692 34–44. 10.1016/j.brainres.2018.04.023
    1. Matsumoto J., Takata F., Machida T., Takahashi H., Soejima Y., Funakoshi M., et al. (2014). Tumor necrosis factor-alpha-stimulated brain pericytes possess a unique cytokine and chemokine release profile and enhance microglial activation. Neurosci. Lett. 578 133–138. 10.1016/j.neulet.2014.06.052
    1. Mazza M., Marano G., Traversi G., Bria P., Mazza S. (2011). Primary cerebral blood flow deficiency and Alzheimer’s disease: shadows and lights. J. Alzheimers Dis. 23 375–389. 10.3233/jad-2010-090700
    1. McGuire P. G., Rangasamy S., Maestas J., Das A. (2011). Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier. Arterioscler. Thromb. Vasc. Biol. 31 e107–e115. 10.1161/atvbaha.111.235408
    1. Menezes M. J., McClenahan F. K., Leiton C. V., Aranmolate A., Shan X., Colognato H. (2014). The extracellular matrix protein laminin α2 regulates the maturation and function of the blood–brain barrier. J. Neurosci. 34 15260–15280. 10.1523/jneurosci.3678-13.2014
    1. Miners J. S., Kehoe P. G., Love S., Zetterberg H., Blennow K. (2019). CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology. Alzheimers Res. Ther. 11:81. 10.1186/s13195-019-0534-8
    1. Min-Soo K., Bo-Ryoung C., Yong Woo L., Dong-Hee K., Ye Sun H., Won Kyung J., et al. (2018). Chronic cerebral hypoperfusion induces alterations of matrix metalloproteinase-9 and angiopoietin-2 levels in the rat hippocampus. Exp. Neurobiol. 27 299–308. 10.5607/en.2018.27.4.299
    1. Mishra A., Reynolds J. P., Chen Y., Gourine A. V., Rusakov D. A., Attwell D. (2016). Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19 1619–1627. 10.1038/nn.4428
    1. Montagne A., Barnes S. R., Sweeney M. D., Halliday M. R., Sagare A. P., Zhao Z., et al. (2015). Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85 296–302. 10.1016/j.neuron.2014.12.032
    1. Montagne A., Nikolakopoulou A. M., Zhao Z., Sagare A. P., Si G., Lazic D., et al. (2018). Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat. Med. 24 326–337. 10.1038/nm.4482
    1. Morris A. W., Sharp M. M., Albargothy N. J., Fernandes R., Hawkes C. A., Verma A., et al. (2016). Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 131 725–736. 10.1007/s00401-016-1555-z
    1. Muller W. A. (2002). Leukocyte-endothelial cell interactions in the inflammatory response. Lab. Invest. 82 521–534. 10.1038/labinvest.3780446
    1. Munk A., Wang W., Bèchet N., Eltanahy A. M., Cheng A., Sigurdsson B., et al. (2019). PDGF-B Is required for development of the glymphatic system. Cell Rep. 26 2955–2969.e3. 10.1016/j.celrep.2019.02.050
    1. Murfee W. L., Skalak T. C., Peirce S. M. (2005). Differential arterial/venous expression of NG2 proteoglycan in perivascular cells along microvessels: identifying a venule−specific phenotype. Microcirculation 12 151–160. 10.1080/10739680590904955
    1. Nakagawa S., Deli M. A., Kawaguchi H., Shimizudani T., Shimono T., Kittel A., et al. (2009). A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem. Int. 54 253–263. 10.1016/j.neuint.2008.12.002
    1. Nakagomi T., Kubo S., Nakano-Doi A., Sakuma R., Lu S., Narita A., et al. (2015a). Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. Stem Cells (Dayton, Ohio) 33 1962–1974. 10.1002/stem.1977
    1. Nakagomi T., Nakano-Doi A., Kawamura M., Matsuyama T. (2015b). Do vascular pericytes contribute to neurovasculogenesis in the central nervous system as multipotent vascular stem cells? Stem Cells Dev. 24 1730–1739. 10.1089/scd.2015.0039
    1. Nation D. A., Sweeney M. D., Montagne A., Sagare A. P., D’Orazio L. M., Pachicano M., et al. (2019). Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25 270–276. 10.1038/s41591-018-0297-y
    1. Nehls V., Drenckhahn D. (1991). Heterogeneity of microvascularpericytes for smooth muscle type alpha-actin. J. Cell Biol. 113 147–154.
    1. Nehls V., Drenckhahn D. (1993). The versatility of microvascular pericytes: from mesenchyme to smooth muscle ? Histochemistry 99 1–12.
    1. Neuhaus A. A., Couch Y., Sutherland B. A., Buchan A. M. (2017). Novel method to study pericyte contractility and responses to ischaemia in vitro using electrical impedance. J. Cereb. Blood Flow Metab. 37 2013–2024. 10.1177/0271678X16659495
    1. Nikolakopoulou A. M., Montagne A., Kisler K., Dai Z., Wang Y., Huuskonen M. T., et al. (2019). Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat. Neurosci. 22 1089–1098. 10.1038/s41593-019-0434-z
    1. Nishimura A., Ago T., Kuroda J., Arimura K., Tachibana M., Nakamura K., et al. (2016). Detrimental role of pericyte Nox4 in the acute phase of brain ischemia. J. Cereb. Blood Flow Metab. 36 1143–1154. 10.1177/0271678X15606456
    1. Nomura Y., Faegle R., Hori D., Al-Qamari A., Nemeth J. A., Gottesman R., et al. (2018). Cerebral small vessel, but not large vessel disease, is associated with impaired cerebral autoregulation during cardiopulmonary bypass. Anesth. Analg. 127 1314–1322. 10.1213/ane.0000000000003384
    1. Nonaka H., Akima M., Hatori T., Nagayama T., Zhang Z., Ihara F. (2003). The microvasculature of the cerebral white matter: arteries of the subcortical white matter. J. Neuropathol. Exp. Neurol. 62 154–161. 10.1093/jnen/62.2.154
    1. Nortley R., Korte N., Izquierdo P., Hirunpattarasilp C., Mishra A., Jaunmuktane Z., et al. (2019). Amyloid beta oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365:eaav9518. 10.1126/science.aav9518
    1. O’Farrell F. M., Mastitskaya S., Hammond-Haley M., Freitas F., Wah W. R., Attwell D. (2017). Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. eLife 6:e29280. 10.7554/elife.29280
    1. Ogura S., Kurata K., Hattori Y., Takase H., Ishiguro-Oonuma T., Hwang Y., et al. (2017). Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown. JCI Insight 2:e90905. 10.1172/jci.insight.90905
    1. Ohtaki H., Fujimoto T., Sato T., Kishimoto K., Fujimoto M., Moriya M., et al. (2006). “Progressive expression of vascular endothelial growth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat,” in Brain Edema Acta Neurochirurgica Supplementum, Vol. 96 eds Hoff J. T., Keep R. F., Hua Y. (Vienna: Springer; ), 283–287. 10.1007/3-211-30714-1_61
    1. Omote Y., Deguchi K., Kono S., Liu N., Liu W., Kurata T., et al. (2014). Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation. J. Neurosci. Res. 92 369–374. 10.1002/jnr.23327
    1. Onodera O. (2011). What is cerebral small vessel disease? Rinsho Shinkeigaku 51 399–405. 10.5692/clinicalneurol.51.399
    1. Østergaard L., Engedal T. S., Moreton F., Hansen M. B., Wardlaw J. M., Dalkara T., et al. (2016). Cerebral small vessel disease: capillary pathways to stroke and cognitive decline. J. Cereb. Blood Flow Metab. 36 302–325. 10.1177/0271678x15606723
    1. Özen I., Deierborg T., Miharada K., Padel T., Englund E., Genové G., et al. (2014). Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol. 128 381–396. 10.1007/s00401-014-1295-x
    1. Paik J.-H., Skoura A., Chae S.-S., Cowan A. E., Han D. K., Proia R. L., et al. (2004). Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 18 2392–2403. 10.1101/gad.1227804
    1. Park J. H., Hong J. H., Lee S. W., Ji H. D., Jung J. A., Yoon K. W., et al. (2019). The effect of chronic cerebral hypoperfusion on the pathology of Alzheimer’s disease: a positron emission tomography study in rats. Sci. Rep. 9:14102. 10.1038/s41598-019-50681-4
    1. Parkes I., Chintawar S., Cader Z. M. (2018). Neurovascular dysfunction in dementia – human cellular models and molecular mechanisms. Clin. Sci. 132 399–418. 10.1042/cs20160720
    1. Peppiatt C. M., Howarth C., Mobbs P., Attwell D. (2006). Bidirectional control of CNS capillary diameter by pericytes. Nature 443 700–704. 10.1038/nature05193
    1. Pieper C., Marek J., Unterberg M., Schwerdtle T., Galla H.-J. (2014). Brain capillary pericytes contribute to the immune defense in response to cytokines or LPS in vitro. Brain Res. 1550 1–8. 10.1016/j.brainres.2014.01.004
    1. Pieper C., Pieloch P., Galla H. J. (2013). Pericytes support neutrophil transmigration via interleukin-8 across a porcine co-culture model of the blood-brain barrier. Brain Res. 1524 1–11. 10.1016/j.brainres.2013.05.047
    1. Pollock H., Jutchings M., Weller R. O., Zhang E.-T. (1997). Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J. Anat. 191 337–346. 10.1046/j.1469-7580.1997.19130337.x
    1. Pombero A., Garcia-Lopez R., Martinez S. (2016). Brain mesenchymal stem cells: physiology and pathological implications. Dev. Growth Differ. 58 469–480. 10.1111/dgd.12296
    1. Proebstl D., Voisin M.-B., Woodfin A., Whiteford J., D’Acquisto F., Jones G. E., et al. (2012). Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209 1219–1234. 10.1084/jem.20111622
    1. Quaegebeur A., Segura I., Carmeliet P. (2010). Pericytes: blood-brain barrier safeguards against neurodegeneration? Neuron 68 321–323. 10.1016/j.neuron.2010.10.024
    1. Rajani R. M., Ratelade J., Domenga-Denier V., Hase Y., Kalimo H., Kalaria R. N., et al. (2019). Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL. Acta Neuropathol. Commun. 7:187. 10.1186/s40478-019-0844-x
    1. Rajantie I., Ilmonen M., Alminaite A., Ozerdem U., Alitalo K., Salven P. (2004). Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104 2084–2086. 10.1182/blood-2004-01-0336
    1. Renner O., Tsimpas A., Kostin S., Valable S., Petit E., Schaper W., et al. (2003). Time- and cell type-specific induction of platelet-derived growth factor receptor-β during cerebral ischemia. Mol. Brain Res. 113 44–51. 10.1016/S0169-328X(03)00085-8
    1. Ribatti D., Nico B., Crivellato E. (2011). The role of pericytes in angiogenesis. Int. J. Dev. Biol. 55 261–268. 10.1387/ijdb.103167dr
    1. Rouget C. M. (1873). Memoire sur le developpement, de la structure et les proprietes physiologiques des capillaires sanguins et lympha-tiques. Arch. Physiol. Norm. Path. 5 603–663.
    1. Rudziak P., Ellis C. G., Kowalewska P. M. (2019). Role and molecular mechanisms of pericytes in regulation of leukocyte diapedesis in inflamed tissues. Mediat. Inflamm. 2019 1–9. 10.1155/2019/4123605
    1. Rungta R. L., Chaigneau E., Osmanski B.-F., Charpak S. (2018). Vascular compartmentalization of functional hyperemia from the synapse to the pia. Neuron. 99 362–375.e4. 10.1016/j.neuron.2018.06.012
    1. Rustenhoven J., Aalderink M., Scotter E. L., Oldfield R. L., Bergin P. S., Mee E. W., et al. (2016). TGF-beta1 regulates human brain pericyte inflammatory processes involved in neurovasculature function. J. Neuroinflamm. 13:37. 10.1186/s12974-016-0503-0
    1. Rustenhoven J., Jansson D., Smyth L. C., Dragunow M. (2017). Brain pericytes as mediators of neuroinflammation. Trends Pharmacol. Sci. 38 291–304. 10.1016/j.tips.2016.12.001
    1. Ryu J., Petersen M. A., Murray S. G., Baeten K. M., Meyer-Franke A., Chan J. P., et al. (2015). Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat. Commun. 6:8164. 10.1038/ncomms9164
    1. Sagare A. P., Bell R. D., Zhao Z., Ma Q., Winkler E. A., Ramanathan A., et al. (2013). Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4:2932. 10.1038/ncomms3932
    1. Sakuma R., Kawahara M., Nakano-Doi A., Takahashi A., Tanaka Y., Narita A., et al. (2016). Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. J. Neuroinflamm. 13:57. 10.1186/s12974-016-0523-9
    1. Salzman K. L., Osborn A. G., House P., Jinkins J. R., Ditchfield A., Cooper J. A., et al. (2005). Giant tumefactive perivascular spaces. Am. J. Neuroradiol. 26 298–305.
    1. Sandison J. C. (1931). Observations of the circulating blood cells, adventitial (Rouget) cells and muscle cells, endothelium and macrophages in the transparent chamber of the rabbit’s ear. Anat. Rec. 50 355–379.
    1. Schultz N., Byman E., Fex M., Wennström M. (2017). Amylin alters human brain pericyte viability and NG2 expression. J. Cereb. Blood Flow Metab. 37 1470–1482. 10.1177/0271678x16657093
    1. Sengillo J. D., Winkler E. A., Walker C. T., Sullivan J. S., Johnson M., Zlokovic B. V. (2013). Deficiency in mural vascular cells coincides with blood–brain barrier disruption in Alzheimer’s disease. Brain Pathol. 23 303–310. 10.1111/bpa.12004
    1. Seo J., Maki T., Maeda M., Miyamoto N., Liang A. C., Hayakawa K., et al. (2014). Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling. PLoS One 9:e103174. 10.1371/journal.pone.0103174
    1. Seo J., Miyamoto N., Hayakawa K., Pham L.-D. D., Maki T., Ayata C., et al. (2013). Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury. J. Clin. Invest. 123 782–786. 10.1172/jci65863
    1. Shane P. H., Didier Y. R. S. (2011). Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol. 12 551–564. 10.1038/nrm3176
    1. Shen J., Xu G., Zhu R., Yuan J., Ishii Y., Hamashima T., et al. (2019). PDGFR-β restores blood-brain barrier functions in a mouse model of focal cerebral ischemia. J. Cereb. Blood Flow Metab. 39 1501–1515. 10.1177/0271678x18769515
    1. Shibata M., Yamada S., Kumar R. S., Calero M., Bading J., Frangione B., et al. (2000). Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier. J. Clin. Invest. 106 1489–1499. 10.1172/jci10498
    1. Shigemoto-Mogami Y., Hoshikawa K., Sato K. (2018). Activated microglia disrupt the blood-brain barrier and induce chemokines and cytokines in a rat in vitro model. Front. Cell Neurosci. 12:494. 10.3389/fncel.2018.00494
    1. Silva M., Lange S., Hinrichsen B., Philp A. R., Reyes C. R., Halabi D., et al. (2019). Pericytes favor oligodendrocyte fate choice in adult neural stem cells. Front. Cell. Neurosci. 13:85. 10.3389/fncel.2019.00085
    1. Simpkins A. N., Dias C., Leigh R., Benson R. T., Hsia A. W., Latour L. L., et al. (2016). Identification of reversible disruption of the human blood–brain barrier following acute ischemia. Stroke 47 2405–2408. 10.1161/strokeaha.116.013805
    1. Smith A. J., Yao X., Dix J. A., Jin B. J., Verkman A. S. (2017). Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife 6:e27679. 10.7554/eLife.27679
    1. Smyth L., Rustenhoven J., Scotter E. L., Schweder P., Faull R., Park T., et al. (2018). Markers for human brain pericytes and smooth muscle cells. J. Chem. Neuroanat. 92 48–60. 10.1016/j.jchemneu.2018.06.001
    1. Smyth L. C. D., Rustenhoven J., Park T., Schweder P., Jansson D., Heppner P. A., et al. (2018). Unique and shared inflammatory profiles of human brain endothelia and pericytes. J. Neuroinflamm. 15:138. 10.1186/s12974-018-1167-8
    1. Song S., Ewald A. J., Stallcup W., Werb Z., Bergers G. (2005). PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat. Cell Biol. 7 870–879. 10.1038/ncb1288
    1. Spector R., Robert Snodgrass S., Johanson C. E. (2015). A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp. Neurol. 273 57–68. 10.1016/j.expneurol.2015.07.027
    1. Stapor P. C., Sweat R. S., Dashti D. C., Betancourt A. M., Murfee W. (2014). Pericyte dynamics during angiogenesis: new insights from new identities. J. Vasc. Res. 51 163–174. 10.1159/000362276
    1. Stark K., Eckart A., Haidari S., Tirniceriu A., Lorenz M., von Brühl M.-L., et al. (2013). Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat. Immunol. 14 41–51. 10.1038/ni.2477
    1. Staszewski J., Piusiñska-Macoch R., Brodacki B., Skrobowska E., Macek K., Stêpieñ A. (2017). Risk of vascular events in different manifestations of cerebral small vessel disease: a 2-year follow-up study with a control group. Heliyon 3:e00455. 10.1016/j.heliyon.2017.e00455
    1. Stebbins M. J., Gastfriend B. D., Canfield S. G., Lee M.-S., Richards D., Faubion M. G., et al. (2019). Human pluripotent stem cell–derived brain pericyte–like cells induce blood-brain barrier properties. Sci. Adv. 5:eaau7375. 10.1126/sciadv.aau7375
    1. Sundberg C., Kowanetz M., Brown L. F., Detmar M., Dvorak H. F. (2002). Stable expression of angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab. Invest. 82 387–401. 10.1038/labinvest.3780433
    1. Sweeney M. D., Ayyadurai S., Zlokovic B. V. (2016). Pericytes of the neurovascular unit‘ey functions and signaling pathways. Nat. Neurosci. 19 771–783. 10.1038/nn.4288
    1. Sweeney M. D., Kisler K., Montagne A., Toga A. W., Zlokovic B. V. (2018). The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci. 21 1318–1331. 10.1038/s41593-018-0234-x
    1. Tachibana M., Yamazaki Y., Liu C.-C., Bu G., Kanekiyo T. (2018). Pericyte implantation in the brain enhances cerebral blood flow and reduces amyloid-β pathology in amyloid model mice. Exp. Neurol. 300 13–21. 10.1016/j.expneurol.2017.10.023
    1. Takagi T., Imai T., Mishiro K., Ishisaka M., Tsujimoto M., Ito H., et al. (2017). Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood-brain barrier. J. Cereb. Blood Flow Metab. 37 123–139. 10.1177/0271678X15621499
    1. Tallquist M. D., French W. J., Soriano P. (2003). Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1:E52. 10.1371/journal.pbio.0000052
    1. Teichert M., Milde L., Holm A., Stanicek L., Gengenbacher N., Savant S., et al. (2017). Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat. Commun. 8:16106. 10.1038/ncomms16106
    1. Theriault P., ElAli A., Rivest S. (2016). High fat diet exacerbates Alzheimer’s disease-related pathology in APPswe/PS1 mice. Oncotarget 7 67808–67827. 10.18632/oncotarget.12179
    1. Thomas H., Cowin A. J., Mills S. J. (2017). The Importance of pericytes in healing: wounds and other pathologies. Int. J. Mol. Sci. 18:1129. 10.3390/ijms18061129
    1. Thurgur H., Pinteaux E. (2019). Microglia in the neurovascular unit: blood-brain barrier-microglia interactions after central nervous system disorders. Neuroscience 405 55–67. 10.1016/j.neuroscience.2018.06.046
    1. Tsai H.-H., Niu J., Munji R., Davalos D., Chang J., Zhang H., et al. (2016). Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 351 379–384. 10.1126/science.aad3839
    1. Uemura M. T., Ihara M., Maki T., Nakagomi T., Kaji S., Uemura K., et al. (2018). Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion. Brain Pathol. 28 521–535. 10.1111/bpa.12523
    1. Ueno M., Tomimoto H., Akiguchi I., Wakita H., Sakamoto H. (2002). Blood–brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J. Cereb. Blood Flow Metab. 22 97–104. 10.1097/00004647-200201000-00012
    1. Underly R. G., Levy M., Hartmann D. A., Grant R. I., Watson A. N., Shih A. Y. (2017). Pericytes as inducers of rapid, matrix metalloproteinase-9-dependent capillary damage during ischemia. J. Neurosci. 37 129–140. 10.1523/Jneurosci.2891-16.2016
    1. Ushiwata I., Ushiki T. (1990). Cytoarchitecture of the smooth muscles and pericytes of rat cerebral blood vessels. J. Neurosurg. 73 82–90. 10.3171/jns.1990.73.1.0082
    1. Vanlandewijck M., He L., Mäe M., Andrae J., Ando K., Gaudio F., et al. (2018). A molecular atlas of cell types and zonation in the brain vasculature. Nature 554 475–480. 10.1038/nature25739
    1. Walshe T. E., Saint-Geniez M., Maharaj A. S., Sekiyama E., Maldonado A. E., D’Amore P. A. (2009). TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS One 4:e5149. 10.1371/journal.pone.0005149
    1. Wan Y., Jin H. J., Zhu Y. Y., Fang Z., Mao L., He Q., et al. (2018). MicroRNA-149-5p regulates blood–brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes. FASEB J. 32 3133–3148.
    1. Winkler E. A., Bell R. D., Zlokovic B. V. (2010). Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 5:32. 10.1186/1750-1326-5-32
    1. Winkler E. A., Bell R. D., Zlokovic B. V. (2011a). Lack of smad or notch leads to a fatal game of brain pericyte hopscotch. Dev. Cell. 20 279–280. 10.1016/j.devcel.2011.03.002
    1. Winkler E. A., Bell R. D., Zlokovic B. V. (2011b). Central nervous system pericytes in health and disease. Nat. Neurosci. 14 1398–1405. 10.1038/nn.2946
    1. Winkler E. A., Sagare A. P., Zlokovic B. V. (2014). The pericyte: a forgotten cell type with important implications for Alzheimer’s disease? Brain Pathol. 24 371–386. 10.1111/bpa.12152
    1. Winkler E. A., Sengillo J. D., Sullivan J. S., Henkel J. S., Appel S. H., Zlokovic B. V. (2013). Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125 111–120. 10.1007/s00401-012-1039-8
    1. Wong S.-P., Rowley J. E., Redpath A. N., Tilman J. D., Fellous T. G., Johnson J. R. (2015). Pericytes, mesenchymal stem cells and their contributions to tissue repair. Pharmacol. Ther. 151 107–120. 10.1016/j.pharmthera.2015.03.006
    1. Xing C.-Y., Tarumi T., Liu J., Zhang Y., Turner M., Riley J., et al. (2017). Distribution of cardiac output to the brain across the adult lifespan. J. Cereb. Blood Flow Metab. 37 2848–2856. 10.1177/0271678x16676826
    1. Yamada M., Ihara M., Okamoto Y., Maki T., Washida K., Kitamura A., et al. (2011). The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in APP overexpressing mice. PLoS One 6:e16567. 10.1371/journal.pone.0016567
    1. Yamazaki Y., Kanekiyo T. (2017). Blood-brain barrier dysfunction and the pathogenesis of Alzheimer’s disease. Int. J. Mol. Sci. 18:1965. 10.3390/ijms18091965
    1. Yanagida K., Liu C. H., Faraco G., Galvani S., Smith H. K., Burg N., et al. (2017). Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc. Natl. Acad. Sci. U.S.A. 114 4531–4536. 10.1073/pnas.1618659114
    1. Yang S., Jin H., Zhu Y., Wan Y., Opoku E., Zhu L., et al. (2017). Diverse functions and mechanisms of pericytes in ischemic stroke. Curr. Neuropharmacol. 15 892–905. 10.2174/1570159x15666170112170226
    1. Yang Y., Andersson P., Hosaka K., Zhang Y., Cao R., Iwamoto H., et al. (2016). The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages. Nat. Commun. 7:11385. 10.1038/ncomms11385
    1. Yao Y., Chen Z.-L., Norris E. H., Strickland S. (2014). Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat. Commun. 5:3413. 10.1038/ncomms4413
    1. Yemisci M., Gursoy-Ozdemir Y., Vural A., Can A., Topalkara K., Dalkara T. (2009). Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15 1031–1037. 10.1038/nm.2022
    1. Yokota K., Kobayakawa K., Saito T., Hara M., Kijima K., Ohkawa Y., et al. (2017). Periostin promotes scar formation through the interaction between pericytes and infiltrating monocytes/macrophages after spinal cord injury. Am. J. Pathol. 187 639–653. 10.1016/j.ajpath.2016.11.010
    1. Yuan H., Khankin E. V., Karumanchi A. S., Parikh S. M. (2009). Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol. Cell. Biol. 29 2011–2022. 10.1128/mcb.01472-08
    1. Zechariah A., ElAli A., Doeppner T. R., Jin F., Hasan M. R., Helfrich I., et al. (2013). Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke 44 1690–1697. 10.1161/STROKEAHA.111.000240
    1. Zeisel A., Hochgerner H., Lönnerberg P., Johnsson A., Memic F., Zwan J. V. D., et al. (2018). Molecular architecture of the mouse nervous system. Cell 174 999–1014.e1022. 10.1016/j.cell.2018.06.021
    1. Zenaro E., Piacentino G., Constantin G. (2017). The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 107 41–56. 10.1016/j.nbd.2016.07.007
    1. Zenker D., Begley D., Bratzke H., Rübsamen-Waigmann H., von Briesen H. (2003). Human blood-derived macrophages enhance barrier function of cultured primary bovine and human brain capillary endothelial cells. J. Physiol. 551 1023–1032. 10.1113/jphysiol.2003.045880
    1. Zhang E.-T., Richards H. K., Kida S., Weller R. O. (1990). Interrelationships ofthe pia mater and the perivascular (Virchow-Robin) spaces in thehuman cerebrum. J. Anat. 170 111–123.
    1. Zhang L., Tan J., Jiang X., Qian W., Yang T., Sun X., et al. (2017). Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy. Biol. Res. 50:26. 10.1186/s40659-017-0130-y
    1. Zhao Z., Nelson A. R., Betsholtz C., Zlokovic B. V. (2015). Establishment and dysfunction of the blood-brain barrier. Cell 163 1064–1078. 10.1016/j.cell.2015.10.067
    1. Zheng Gang Z., Li Z., Quan J., Ruilan Z., Kenneth D., Cecylia P., et al. (2000). VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Invest. 106 829–838. 10.1172/jci9369
    1. Zhou Y., Peng Z., Seven E. S., Leblanc R. M. (2018). Crossing the blood-brain barrier with nanoparticles. J Control. Release 270 290–303. 10.1016/j.jconrel.2017.12.015
    1. Zhu Y., Soderblom C., Krishnan V., Ashbaugh J., Bethea J. R., Lee J. K. (2015). Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol. Dis. 74 114–125. 10.1016/j.nbd.2014.10.024
    1. Zimmermann K. W. (1923). Der feinere bau der blutcapillaren. Z. Anat. Entwicklungsgesch. 68 29–109. 10.1007/bf02593544
    1. Zlokovic B. V., Deane R., Sagare A. P., Bell R. D., Winkler E. A. (2010). Low−density lipoprotein receptor−related protein−1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β−peptide elimination from the brain. J. Neurochem. 115 1077–1089. 10.1111/j.1471-4159.2010.07002.x
    1. Zweifach B. W. (1934). A micro-manipulative study of blood capillaries. Anat. Rec. 59 83–108.

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