Revisiting the neurovascular unit

Nature Neuroscience, Journal Year: 2021, Volume and Issue: 24(9), P. 1198 - 1209

Published: Aug. 5, 2021

Language: Английский

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Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

Frontiers in Aging Neuroscience, Journal Year: 2020, Volume and Issue: 12

Published: April 14, 2020

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

Language: Английский

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Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Aug. 19, 2021

The blood-brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of neural tissue. It separates peripheral circulatory system from brain parenchyma while facilitating communication. Alterations distinct physiological properties BBB lead to breakdown associated with normal aging and various neurodegenerative diseases. In this review, we first briefly discuss process, then review phenotypes mechanisms that further cause neurodegeneration cognitive impairments. We also summarize dementia such as Alzheimer's disease (AD) vascular (VaD) subsequently disruption correlated cognition decline. Overlaps between AD VaD are discussed. Techniques could identify biomarkers summarized. Finally, concluded be used an emerging biomarker assist diagnose impairment dementia.

Language: Английский

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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

Circulation Research, Journal Year: 2020, Volume and Issue: 128(4)

Published: Dec. 30, 2020

Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described several brain disorders, genetically induced pericyte deficiency the leads to increased macromolecular leakage across blood-brain barrier (BBB). However, molecular details endothelial response remain elusive. Objective: To map transcriptional changes resulting from lack contact at single-cell level correlate them with regional heterogeneities BBB function vascular phenotype. Methods Results: We reveal transcriptional, morphological, functional consequences absence for using combination methodologies, including RNA sequencing, tracer analyses, immunofluorescent detection protein expression pericyte-deficient adult Pdgfb ret/ret mice. find that without retain general BBB-specific gene profile, however, they acquire venous-shifted pattern become transformed regarding numerous growth factors regulatory proteins. Adult brains display ongoing angiogenic sprouting concomitant cell proliferation providing unique insights into tip transcriptome. also heterogeneous modes impairment, where hotspot sites arteriolar-shifted identity pinpoint putative regulators. By testing causal involvement some these reverse genetics, we uncover reinforcing angiopoietin 2 BBB. Conclusions: elucidating complexity cellular resolution, our study provides insight importance arterio-venous zonation, quiescence, limited set functions. The BBB-reinforcing ANGPT2 (angiopoietin 2) is paradoxical given its wider as TIE2 (TEK receptor tyrosine kinase) antagonist may suggest context-dependent brain.

Language: Английский

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Pericyte Control of Blood Flow Across Microvascular Zones in the Central Nervous System

Annual Review of Physiology, Journal Year: 2021, Volume and Issue: 84(1), P. 331 - 354

Published: Oct. 21, 2021

The vast majority of the brain's vascular length is composed capillaries, where our understanding blood flow control remains incomplete. This review synthesizes current knowledge on across microvascular zones by addressing issues with nomenclature and drawing new developments from in vivo optical imaging single-cell transcriptomics. Recent studies have highlighted important distinctions mural cell morphology, gene expression, contractile dynamics, which can explain observed differences response to vasoactive mediators between arteriole, transitional, capillary zones. Smooth muscle cells arterioles ensheathing pericytes arteriole-capillary transitional zone large-scale, rapid changes flow. In contrast, downstream act slower smaller scales are involved establishing resting tone heterogeneity. Many unresolved remain, including that activate different pericyte types vivo, role pericyte-endothelial communication conducting signals capillaries arterioles, how neurological disease affects these mechanisms.

Language: Английский

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Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Science, Journal Year: 2022, Volume and Issue: 375(6582)

Published: Feb. 17, 2022

The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore function are lacking. An attractive strategy repurpose developmental regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use Wnt ligands complicated by their pleiotropic Frizzled signaling activities. Taking advantage Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a BBB-specific activators. In “hit-and-run” adeno-associated virus–assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that specificity adjustable defines modality treat disorders normalizing BBB.

Language: Английский

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Changing demography and the challenge of dementia in India

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(12), P. 747 - 758

Published: Oct. 18, 2021

Language: Английский

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Current state and guidance on arterial spin labeling perfusion MRI in clinical neuroimaging

Magnetic Resonance in Medicine, Journal Year: 2023, Volume and Issue: 89(5), P. 2024 - 2047

Published: Jan. 25, 2023

This article focuses on clinical applications of arterial spin labeling (ASL) and is part a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update expand recommendations provided 2015 ASL consensus paper. Although paper general guidelines MRI, there was lack guidance disease‐specific parameters. Since that time, availability demand MRI has increased. position provides using specific scenarios, including acute ischemic stroke steno‐occlusive disease, arteriovenous malformations fistulas, brain tumors, neurodegenerative seizures/epilepsy, pediatric neuroradiology applications, focusing considerations sequence optimization interpretation. We present several neuroradiological which unique information essential making diagnosis. intended anyone interested routine setting (i.e., single‐subject basis rather than cohort studies) building previous review.

Language: Английский

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Pericytes in the disease spotlight

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(1), P. 58 - 71

Published: July 18, 2023

Molecular and functional pericyte studies at single-cell resolution are providing new insights into long-standing questions about heterogeneity.Pericytes not identified by a single marker but instead gene expression signatures that show substantial inter-organ differences.Pericytes orchestrate precede endothelial cell responses during angiogenesis.Pericyte degeneration dysfunction, triggered the onset of some diseases, contribute to progression those diseases in both vascular non-vascular contexts.The number with dysfunction continues expand, thereby anticipating promising future for pericyte-focused therapy. Pericytes classically defined as mural cells (see Glossary) envelop endothelium small caliber blood vessels, so-called capillaries. embedded within same basement membrane (ECs) interact closely them [1.Armulik A. et al.Pericytes: developmental, physiological, pathological perspectives, problems, promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm al.Microvascular organotypic heterogeneity plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract (63) Scholar]. By contrast, smooth muscle (vSMCs), other type, cover large arteries veins, physically separated from an intimal layer extracellular matrix (ECM). Of note, lymphatic capillaries lack pericytes under physiological conditions, although collecting vessels contain vSMCs [3.Petrova T.V. Koh G.Y. Biological functions vessels.Science. 2020; 369eaax4063Crossref (144) A fundamental function is regulate stabilization vessels. It therefore surprising loss were linked several including cancer cerebrovascular more than decade ago [4.Martin J.D. al.Normalizing tumor vessels: progress, opportunities, challenges.Annu. Rev. Physiol. 2019; 81: 505-534Crossref (242) Scholar,5.Lendahl U. al.Emerging links between neurodegenerative diseases-a special role pericytes.EMBO Rep. 20e48070Crossref (71) However, therapies have been poorly explored. Instead, most on vascular-directed therapeutic strategies ECs – central components build Emerging data are, however, changing perception mere supporting recruited final stage vessel formation essential elements early phases angiogenesis anticipate EC behavior. In addition, recent research revealing novel roles beyond their implications vasculature. Collectively, we believe these open exciting avenues approaches call broader understanding disease progression. We provide here global overview significant advances regarding our different pathobiological scenarios discuss field's current paradigms controversies. First, address associated responses. Second, evidence disease, cell-autonomous For comprehensive details biology, ontology, specific signaling pathways, refer reader importance, emerging concepts biology described following sections only studied one tissue. To avoid confusion generalizability properties, frame each considering relevant organ study. exhibit inter- intra-tissue molecular differences exert tissue-specific [2.Holm Their molecular, morphological, inextricably diverse developmental origins, modes recruitment, anatomical localization. example, nervous system (CNS) microvasculature firmly continuously invested around support barrier whereas liver pericytes, commonly referred hepatic stellate (HSCs), reside perisinusoidal space, loosely discontinuously ECs, hold unique vitamin storage capacity meet demands, distribution density variable among organs beds, CNS showing greatest pericyte-to-EC abundance. From standpoint there no can exclusively identify (Box 1), albeit emergence techniques shedding light markers functions. first atlas types brain adult mice RNA sequencing (scRNA-seq) revealed follow gradient transitional phenotypes. This occurs interface precapillary arterioles, capillaries, postcapillary venules, does continuum along arteriovenous axis (Figure 1 Box 1) [6.Vanlandewijck M. al.A zonation vasculature.Nature. 554: 475-480Crossref (876) Whether this phenotypes specifically restricted vasculature or also present beds remains be determined. Indeed, many 2 illustrates three top-ranked enriched per organ), which transporters contractile machinery [7.Muhl L. al.Single-cell analysis uncovers fibroblast criteria identification discrimination.Nat. Commun. 11: 3953Crossref (187) Another intriguing observation cross-organ Scholar,8.Muhl transcriptomic inventory murine cells.Dev. 2022; 57: 2426-2443Abstract Currently, inter-tissue behavior two main completely understood. may because greater cell-intrinsic plasticity adapt portfolio fulfill universal across tissues. contrast differences, transcription factors appears relatively conserved organs, suggesting subtypes epigenetic mechanisms Accordingly, DNA hypermethylation was recently found control alpha actin (αSMA) renal after ischemia [9.Chou Y.H. al.Methylation acute injury promotes chronic kidney disease.J. Clin. Invest. 130: 4845-4857Crossref (18) indicates methods such assay transposase-accessible chromatin (ATAC-seq) will instrumental further understand phenotypes.Box 1Unraveling identity pericytesThe challenging task. Despite ongoing efforts, consensus unambiguous identification. date all distinguish types, scRNA-seq now opportunities discern tissue specificity Scholar,71.Teuwen L.A. al.Tumor co-option probed analysis.Cell 2021; 35109253Abstract (35) Scholar,93.Baek S.H. al.Single reveals identities.Front Cardiovasc. Med. 9876591Crossref (9) The use transgenic reporter mouse models has label, trace, locate populations vivo. combination multiple lines often necessary properly discriminate perivascular Scholar, 7.Muhl 8.Muhl Mural highly plastic cells; phenotypic do Figure 1A,B text) transcriptional point view, distinct continuums cells: (i) capillary venous (SMCs), where gradually transition SMC phenotype, (ii) arterial SMCs pattern towards arteriole SMCs. resemblance venular Scholar], well classic led hypothesis transcriptionally morphologically similar Human recapitulate pattern, human evenly distributed over veins [50.Yang A.C. mediators Alzheimer's risk.Nature. 603: 885-892Crossref (117) Scholar,94.Garcia F.J. dissection 893-899Crossref (53) Unlike separation brain, discerned functionality marked solute transport (ECM) organization Unfortunately, ability predict presence limited, select few retain adequate specificity. zebrafish better alternative study genes [95.Shih al.Integrated identifies signature zebrafish.Development. 148dev200189Crossref (4) RGS5, NDUFA4L2, KNCJ8, HIGD1B, ABCC9, NOTCH3, PDGFRB currently species markers, detailed characterization when studying text).Figure 2Organotypic markers.Show full captionThis figure summarizes heart, lung, kidney, colon (upper row) (lower row). Pericyte chosen based stringent evaluation abundance, specificity, homogeneity utilizing information provided Scholar,50.Yang Scholar,82.Muhl al.The SARS-CoV-2 receptor ACE2 expressed COVID-19 research.Stem 17: 1089-1104Abstract (0) Scholar,84.Dobie R. transcriptomics mesenchyme fibrosis.Cell 29: 1832-1847Abstract (164) Scholar,85.Kuppe C. al.Decoding myofibroblast origins fibrosis.Nature. 589: 281-286Crossref (225) Scholar,95.Shih Scholar,100.Winkler E.A. normal malformed vasculature.Science. 375: eabi7377Crossref (5) 101.Travaglini K.J. lung sequencing.Nature. 587: 619-625Crossref (470) 102.Kinchen J. al.Structural remodeling colonic inflammatory bowel disease.Cell. 175: 372-386Abstract (313) Validation selected situ used second selection.View Large Image ViewerDownload Hi-res image Download (PPT) text). selection. Many documented [10.Potente al.Basic aspects angiogenesis.Cell. 146: 873-887Abstract (1978) historical view proposes mainly late stages Scholar,10.Potente taking advantage retina paradigmatic experimental model angiogenesis, concept challenged [11.Park D.Y. al.Plastic blood-retinal barrier.Nat. 2017; 8: 15296Crossref (175) 12.Figueiredo A.M. al.Phosphoinositide 3-kinase-regulated maturation governs remodeling.Circulation. 142: 688-704Crossref (25) 13.Orlich M.M. al.Mural SRF controls migration, patterning flow.Circ. Res. 131: 308-327Crossref 14.Dieguez-Hurtado al.Loss factor RBPJ induces disease-promoting properties pericytes.Nat. 10: 2817Crossref 15.Teichert al.Pericyte-expressed Tie2 maturation.Nat. 16106Crossref (174) 16.Eilken H.M. al.Pericytes VEGF-induced sprouting through VEGFR1.Nat. 1574Crossref (134) showed that, yet achieved maturity seen formed permissive cell-cycle progression, morphological adaptation, migration [12.Figueiredo Scholar,13.Orlich setting, growth precedes expansion it still unclear why. One possibility expanding rapidly, ensure production sufficient signals, coherent inhibition activation blocks proliferation Scholar] nuclear translocation FOXO1 master regulator quiescence [17.Kobialka P. Graupera Revisiting PI3-kinase signalling angiogenesis.Vasc. 1: H125-H134Crossref examined absent, become angiogenic able proliferate [18.Mae M.A. blood–brain response loss.Circ. 128: e46-e62Crossref require expand. Nonetheless, fair acknowledge shown reduced coverage leads increased [19.Dave J.M. al.Pericyte ALK5/TIMP3 contributes morphogenesis developing brain.Dev. 47: 388-389Abstract (8) Although discrepancies highlight pericyte–EC interactions complex, they explained animal genetic interfere pericytes. Importantly, behaviors mostly tissues belonging CNS. Hence, given high abundance CNS, possible substantially outnumber them. interesting immature remain close contact entirety Scholar,20.Crouch E.E. al.Ensembles promote prenatal brain.Cell. 185: 3753-3769Abstract (11) suggests communication relies paracrine juxtracrine signaling, explain why Pu

Language: Английский

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Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

EMBO Reports, Journal Year: 2019, Volume and Issue: 20(11)

Published: Oct. 16, 2019

Review16 October 2019Open Access Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes Urban Lendahl Department of Cell Molecular Biology, Karolinska Institutet, Stockholm, Sweden Neurobiology, Care Sciences Society, Division Neurogeriatrics, Center Alzheimer Research, Solna, Integrated Cardio Metabolic Centre (ICMC), Huddinge, Search more papers by this author Per Nilsson Christer Betsholtz Corresponding Author [email protected] orcid.org/0000-0002-8494-971X Immunology, Genetics Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Medicine, Information Lendahl1,2,3, Nilsson2 *,3,4,5 1Department 2Department 3Integrated 4Department 5Department *Corresponding author. Tel: +46 709 796690; E-mail: EMBO Reports (2019)20:e48070https://doi.org/10.15252/embr.201948070 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Neurodegenerative diseases cause considerable human suffering, therapy options these two disease categories are limited or non-existing. It is an emerging notion that linked several ways, review, we discuss current status regarding vascular dysregulation disease, conversely, how associated with central nervous system (CNS) degeneration dysfunction. The reviewed a particular focus on pericytes—important cells ensheath endothelium microvasculature which pivotal blood–brain barrier function cerebral blood flow. Finally, address novel molecular cellular insights into other cell types may open new avenues diagnosis development important diseases. 20-HETE 20-Hydroxyeicosatetraenoic acid AD Alzheimer's ALK5 TGFβ type I receptor kinase ALS amyotrophic lateral sclerosis APOE apolipoprotein E APP amyloid precursor protein Aqp4 aquaporin 4 atp adenosine triphosphate a-v arterio-venous avm arteriovenous malformations aβ β peptide BBB BDNF brain-derived neurotrophic factor CAA angiopathy CADASIL autosomal dominant arteriopathy subcortical infarcts leukoencephalopathy CARASIL recessive CBF flow Cldn claudin CNS CSF cerebrospinal fluid CXCL12 C-X-C motif chemokine 12 CXCR4 ECM extracellular matrix EM electron microscopy FGF fibroblast growth GFAP glial fibrillary acidic Glut1 glucose transporter 1 HD Huntington's ISF interstitial Lam laminin LRP1 low-density lipoprotein receptor-related MCAM melanoma adhesion molecule MCI mild cognitive impairment NG2 neuron-glial antigen 2 NVU neurovascular unit OPC oligodendrocyte progenitor PDGF platelet-derived PDGFR PET positron-emission tomography PVS perivascular space scRNA-seq single-cell RNA sequencing SMA smooth muscle actin SOD1 super oxide dismutase SVD small vessel TBI traumatic brain injury TGF transforming tPA tissue plasminogen activator VSMC WML white matter lesions Introduction its vasculature composed 100 billion neurons connected intricate ways. In addition, there even larger number supporting cells, i.e., astrocytes oligodendrocytes, latter forming myelin sheets around making up large part brain. Another category microglia—macrophage-like scavenging debris aggregates, but when activated they also become players inflammation. While traditionally have been classified sub-categories based morphological anatomical criteria differences neurotransmitter repertoire, fine-grained view sub-types now as result recent transcriptomic analyses at level. Thus, than 500 molecularly distinct classes identified mouse 1, 2, information about composition specific regions increasing rapidly 2-8. Insights developmental trajectories different lineages—proceeding from immature progenitors specialized cells—are generated computational transcriptomes derived stages 8-10. Most data thus far mouse, progress made understanding diversity 10. With available normal unperturbed situation benchmark, gene expression changes related start be elucidated, example, (AD) 11 multiple 12, where single-nuclei technology has capture resolution. expected additional diseases, those can faithfully recapitulated models, will transcriptomically analyzed not too distant future. constitutes ≈2% adult body weight receives 20% cardiac output consumes our oxygen glucose. However, it almost negligible capacity long-term storage energy therefore dependent elaborate continuously fuels nutrients. architecture: Feeding arteries follow outer rim via meninges make branches penetrate perpendicularly parenchyma (sometimes referred penetrating arterioles), further split smaller arterioles eventually capillaries (Fig 1A–C). subsequently join venules collect radially oriented veins drain arachnoid 1D). Figure 1. Overview vasculature(A) Schematic dorsal surface feeding (red) draining (blue). (B) Branches superficial vessels, present subarachnoid space, parenchyma. (C) sagittal section level indicated (A) depicted cortex. (D) High-magnification schematic arteriole capillaries. rejoin organized venules, arachnoid. cross-sections vessels arteriolar, capillary, venous levels indicated, depicting various vessel-associated (as figure), spaces transport veins. longitudinal stretch capillary illustrates single pericyte connects endothelial through peg-socket contacts. Download figure PowerPoint built principal types: inner lining surrounded layer mural cells. phenotypes called names depending type: (VSMC) cover arteries, arterioles, veins, (Figs 1D 2). proportion abluminal covered varies among types. coverage complete whereas incomplete microvessels. least (≈10–20%) observed capillaries, (in brain) typically bipolar tripolar branch points) primary processes along length axis capillary. From processes, short sawtooth-like secondary extend. 2. Pericytes unitIn (BBB), interlocked tight junctions adherens junctions, extensively coated A arterial side side, coating (NVU) middle firing neuron sending signals (unknown their chemical nature) local branch, play receiver, turn exerting effects upstream-propagating regulate contraction/relaxation terminal arteriole. For most part, interface area physically separated basement membrane. sites, often located end membranes come close apposition. These sites contacts plaques. contacts, pericytic cytoplasmic projections (“pegs”) protrude membrane pockets (“sockets”), plaques flat areas contact. An question both contact if one thereby potentially integrating functional behavior. structures mostly ultrastructural transmission scanning analysis animal tissues 13, 14, seem form under vitro conditions during pericyte–endothelial co-culture 15. Little is, however, known physiological intriguing possibility harbor gap possibly moieties involved contact-dependent (“juxtacrine”) signaling 16 Although pericyte:endothelial ratio high compared organs, sometimes claimed order 1:1, own unpublished observations suggest density severalfold lower Therefore, fact tube 100% (i.e., would find every cross-section) follows 1B). Since difficult distinguish using light singular mRNA markers, constitute defining criterion versus types, including fibroblasts macrophages. Progress proteomic provide ideas cytoskeletal proteins reside feature serves separate fluids (interstitial fluid; CSF, respectively) hinders pathogens xenobiotic substances entering non-fenestrated physical barrier. This contrasts in, liver, kidney, endocrine fenestrated freely permeable solutes proteins. To allow efficient, precise, regulated ions, sugars, amino acids, nucleic lipids, proteins, equipped wide range influx transporters, well receptors engage receptor-mediated transcytosis. bounce off unwanted neurotoxic blood, xenobiotics taken gut, expresses efflux transporters nonspecifically recognize export lipophilic molecules. major against low pharmaceuticals poses problem efficient drug delivery Whereas features described above attributed surrounding peri-endothelial roles inducers regulators properties taking active homeostatic functions BBB. suggested many molecules specifically expressed lung 17. Among immune fibroblasts, and—depending organ—epithelial deserve attention because appear ubiquitous obligatory component microvessel wall. As mentioned, harbors higher peripheral skeletal muscle, hundredfold (for see ref. 18). magnitude reported should treated caution since identification remains ambiguous, appears enough (or vast majority of) cell. integrity depends astrocytes, completely encapsulate endfeet 19 1B Regulated across largely driven transcytosis discussed below, underpinnings controlled permeability, pericytes, intense research. Platelet-derived critical recruitment, differentiation, homeostasis 18. Hence, evidence importance mainly provided models hypomorphic 20, 21. One such model, Pdgfbret/ret produces only truncated PDGFB ligand (PDGFB-ret) lacking C-terminal residues retention motif. mediates binding secreted wild-type proteoglycans 22. Truncation makes PDGFB-ret unable bind proteoglycans. retains full activate β-receptor (PDGFR-β), increased diffusion away producer cells—the endothelium—presumably lowers concentration vicinity. Pdgfb Pdgfrb genes fully partially ablated. null mutants (heterozygous homozygous) reduction numbers, coupled dysfunction leakage defects 21, 23. More studies demonstrated mice differs 24. Pericyte loss studied another PDGF-signaling impaired PdgfrbF7/F7 mice, reduces competence 25. affected, breakdown was stage were indicating develops rather due 26. engaged complex cross-talk, understood. There ligand–receptor interactions operating PDGF-PDGFR, Ang1-Tie-2, Notch pathway involved, notably regulating PDGFR-β 27. Accordingly, 27-29. Recent work implicated CD146 (MCAM) co-receptor 30. 31 clearly show impairs formation barriers CNS, perturbed do harm 32. has, ablation causes hemorrhage developing embryos, does so without depleting 33. suggests modulation severe phenotype absence 34. worse consequences dropout. underscored reduced above-mentioned nevertheless develop seemingly stable pericyte-deficient attenuation 20. mechanism(s) process hypoplasia unknown, while mechanisms recently study revealing intracellular tubules control 35, unclear whether affects system. what extent affect aspects BBB, unclear. Tight junction claudins, endothelial-specific 5 (Cldn5) 36, limit paracellular interlocking review 37). Available (caused mutants) leads Cldn5 partly inconsistent 38 topic requires study. needs increase nutrient supply given point time active. (CBF) constantly adjusted regions. (NVU), conglomerate VSMC, neurons, regulator connection neuronal activity CBF, allows adjustment response activity, coupling (a.k.a. hyperemia). regulation understood, coupling. advocating regulatory 39-41 42), (although pericytes) 43 44. Erythrocytes themselves influence sensing deformability 45. divergent views deeper warranted. first maps population 46-48. recently, RNA-sequencing (scRNA-seq) transcriptional profiles all microglia reveal graded zonation matches gradual change diameter presumed biophysical parameters pressure sheer, oxygenation, takes place (A-V) axis. contrast transcription showed pattern A-V Here, quite population, well-separated arteriolar profiles, phenotypic conversion VSMC. finding abrupt transition SMC next border following Previous reports shown exhibit morphologies location: morphologically postcapillary reviews refs. 18, 49; Fig unexpected constituted homogenous signs subtypes apparent discrepancy homogeneity heterogeneity captured dual reporter (fluorescent reporters PDGFRβ elements) 17, although dual-labeled brain, possible some subpopulations efficiently strategy. Alternatively, populations fare less sorting enrichment procedures, leading underrepresentation transcriptome set. advent markers systematically addressed. Furthermore discovery ways stain example Neurotrace 500/52 50, complementary explorations transcriptomes. revealed discrepancies certain species cognate protein. Notably, α-smooth (α-SMA) (Acta2) very adds discussion distribution α-SMA pericytes. fail detect immunoreactivity healthy 44, 51-53 promoter 44 differ closer express levels, center bed 51. proposed degraded sample preparation, reason why detected immunohistochemistry situations 54. explored, putative contractile Paravascular addition proper, second fluid-transporting brain—paravascular flow—regulating 1). choroid plexus, transported meninges, drained connections lymphatic dura mater 55. continuous brain's (PVS), thin cavities surround (parenchymal) 56, 57 water, solute, waste product exchange ISF. How paravascular conduits out 58. Furthermore, report shows experimental damage meningeal accumulation aggregates AD-associated (Aβ) 55 tau 59, lymphatics. alternative glymphatic system, removal products lactate, Aβ, 60. ion buffering ISF, clearance sleep state 61. might required “waste” water channel aquaporin-4 (Aqp4) astrocytic 3A). still discussion. correlated astrocyte endfoot–vascular 62, lines Aqp4-deficient tracer depend intact 63. argued solely responsible transport, support notion, uptake rate unaffected arrest 64. Diffusion-driven injected tracers noted 65-68 69). Tracer connect perivenous drainage, routing enter pial-glial exit membranes, going direction 70. relate sleep–wake cycle 71. Aβ (85%) occurs minority bulk 72, 73, similar findings humans 74. conflicting organized, clear research understand detail diseased states. 3. system(A) model interaction t

Language: Английский

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