Pericytes regulate vascular immune homeostasis in the CNS

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(10)

Опубликована: Март 2, 2021

Pericytes regulate the development of organ-specific characteristics brain vasculature such as blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in control leukocyte trafficking adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using pericyte-deficient mice (Pdgfbret/ret ), we show that limit infiltration into during homeostasis autoimmune neuroinflammation. The permissiveness toward Pdgfbret/ret inversely correlates with vessel pericyte coverage. Upon induction experimental encephalomyelitis (EAE), die severe atypical EAE, which can be reversed fingolimod, indicating mortality is due to massive influx immune cells brain. Additionally, administration anti-VCAM-1 anti-ICAM-1 antibodies reduces diminishes severity EAE symptoms mice, proinflammatory endothelium absence facilitates exaggerated Furthermore, presence myelin peptide-specific peripheral T ;2D2tg leads spontaneous neurological paralleled leukocytes These findings indicate intrinsic changes within promote neuroinflammatory disorder.

Язык: Английский

---

Astrocyte Endfeet in Brain Function and Pathology: Open Questions

Annual Review of Neuroscience, Год журнала: 2023, Номер 46(1), С. 101 - 121

Опубликована: Фев. 28, 2023

Astrocyte endfeet enwrap the entire vascular tree within central nervous system, where they perform important functions in regulating blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte contain specialized organelles proteins, including local protein translation machinery highly organized scaffold which anchor channels, transporters, receptors, enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by loss of polarization specific endfoot dysregulation, BBB disruption, altered clearance, or, extreme cases, coverage. A role has been demonstrated or postulated many these conditions. This review provides an overview development, composition, function, pathological changes highlights gaps our knowledge that future research should address.

Язык: Английский

---

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 7, 2022

Abstract Deterioration of brain capillary flow and architecture is a hallmark aging dementia. It remains unclear how loss pericytes in these conditions contributes to dysfunction. Here, we conduct cause-and-effect studies by optically ablating adult aged mice vivo. Focal pericyte induces dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated the brain, result increased heterogeneity networks. A subset affected capillaries experience reduced perfusion due steal. Some stall regress, leading connectivity. Remodeling neighboring restores endothelial coverage vascular tone within days. Pericyte remodeling slower resulting regions persistent dilation. findings link disruption structure. They also identify as therapeutic target preserve dynamics.

Язык: Английский

---

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease

Brain, Год журнала: 2022, Номер 145(7), С. 2276 - 2292

Опубликована: Май 13, 2022

Abstract To match the metabolic demands of brain, mechanisms have evolved to couple neuronal activity vasodilation, thus increasing local cerebral blood flow and delivery oxygen glucose active neurons. Rather than relying on feedback signals such as consumption or glucose, main signalling pathways rely release vasoactive molecules by neurons astrocytes, which act contractile cells. Vascular smooth muscle cells pericytes are associated with arterioles capillaries, respectively, relax induce vasodilation. Much progress has been made in understanding complex neurovascular coupling, but issues contributions capillary astrocyte calcium signal remain contentious. Study coupling is especially important dysregulation a prominent feature Alzheimer’s disease. In this article we will discuss developments controversies finish discussing current knowledge concerning uncoupling

Язык: Английский

---

Pericytes in the disease spotlight

Trends in Cell Biology, Год журнала: 2023, Номер 34(1), С. 58 - 71

Опубликована: Июль 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

Язык: Английский

---

Pericytes and the Control of Blood Flow in Brain and Heart

Annual Review of Physiology, Год журнала: 2023, Номер 85(1), С. 137 - 164

Опубликована: Фев. 10, 2023

Pericytes, attached to the surface of capillaries, play an important role in regulating local blood flow. Using optogenetic tools and genetically encoded reporters conjunction with confocal multiphoton imaging techniques, 3D structure, anatomical organization, physiology pericytes have recently been subject detailed examination. This work has revealed novel functions morphological features such as tunneling nanotubes brain microtubes heart. Here, we discuss state our current understanding roles flow control heart, where may differ due distinct spatiotemporal metabolic requirements these tissues. We also outline concept electro-metabolic signaling, a universal mechanistic framework that links tissue regulation by vascular smooth muscle cells, capillary K ATP Kir2.1 channels primary sensors. Finally, present major unresolved questions how they can be addressed.

Язык: Английский

---

Cellular and molecular mechanisms of the blood–brain barrier dysfunction in neurodegenerative diseases

Fluids and Barriers of the CNS, Год журнала: 2024, Номер 21(1)

Опубликована: Июль 19, 2024

Abstract Background Maintaining the structural and functional integrity of blood–brain barrier (BBB) is vital for neuronal equilibrium optimal brain function. Disruptions to BBB performance are implicated in pathology neurodegenerative diseases. Main body Early indicators multiple disorders humans animal models include impaired stability, regional cerebral blood flow shortfalls, vascular inflammation associated with dysfunction. Understanding cellular molecular mechanisms dysfunction crucial elucidating sustenance neural computations under pathological conditions developing treatments these This paper initially explores definition BBB, along signaling pathways regulating flow, inflammation. Subsequently, we review current insights into dynamics Alzheimer’s disease, Parkinson's amyotrophic lateral sclerosis, sclerosis. The concludes by proposing a unified mechanism whereby contributes disorders, highlights potential BBB-focused therapeutic strategies targets, outlines lessons learned future research directions. Conclusions breakdown significantly impacts development progression diseases, unraveling underlying elucidate how sustained devise approaches.

Язык: Английский

---

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 30, 2024

Abstract Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure function in different brain areas. Here utilize mesoscale microscopy methods vivo imaging to determine detailed changes aged murine cerebrovascular networks. Whole-brain tracing shows an overall ~10% decrease length branching density ~7% increase radii brains. Light sheet 3D immunolabeling reveals increased arteriole tortuosity of Notably, vasculature pericyte densities show selective significant reductions the deep cortical layers, hippocampal network, basal forebrain We find blood extravasation, implying blood-brain barrier Moreover, awake mice demonstrates reduced baseline on-demand oxygenation despite relatively intact neurovascular coupling. Collectively, uncover regional vulnerabilities network physiological that can mediate cognitive decline aging.

Язык: Английский

---

Blood brain barrier: A review of its anatomy and physiology in health and disease

Clinical Anatomy, Год журнала: 2018, Номер 31(6), С. 812 - 823

Опубликована: Апрель 11, 2018

The blood–brain barrier (BBB) is the principal regulator of transport molecules and cells into out central nervous system (CNS). It comprises endothelial cells, pericytes, immune astrocytes, basement membrane, collectively known as neurovascular unit. development involves many complex pathways from all progenitors unit, but timing its formation not entirely known. coordinated activities components unit other tissues ensure that materials required for growth maintenance are allowed CNS while extraneous ones excluded. This review summarizes current knowledge anatomy, development, physiology BBB, alterations occur in disease conditions. Clin. Anat. 31:812–823, 2018. © 2018 Wiley Periodicals, Inc.

Язык: Английский

---

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

EMBO Reports, Год журнала: 2019, Номер 20(11)

Опубликована: Окт. 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

Язык: Английский

---