The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association

Stroke, Journal Year: 2023, Volume and Issue: 54(6)

Published: April 3, 2023

Preservation of brain health has emerged as a leading public priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among cells, meninges, and hematic lymphatic vasculature (the neurovasculome) that is highly relevant to maintenance cognitive function. In this scientific statement, multidisciplinary team experts examines these advances, assesses their relevance disease, identifies knowledge gaps, provides future directions.

Language: Английский

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

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 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.

Language: Английский

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

Brain, Journal Year: 2022, Volume and Issue: 145(7), P. 2276 - 2292

Published: May 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

Language: Английский

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Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments

Stroke, Journal Year: 2023, Volume and Issue: 54(3), P. 661 - 672

Published: Feb. 27, 2023

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular components forming neurovascular unit. This review examines BBB unit changes in normal aging neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy vascular dementia. Increasing evidence indicates dysfunction contributes to neurodegeneration. Mechanisms underlying are outlined (endothelium mediated) as therapeutic target including increasing uptake of systemically delivered therapeutics across BBB, enhancing clearance potential neurotoxic compounds via preventing dysfunction. Finally, need for novel biomarkers addressed.

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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β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(5), P. 854 - 884

Published: April 7, 2023

The two beta-arrestins, beta-arrestin-1 and -2 (systematic names: arrestin-2 -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number cellular signaling pathways physiological functions. were discovered for their ability to disrupt via G protein-coupled receptors (GPCRs) binding activated receptors. However, it is now well recognized both beta-arrestins can also act as direct modulators numerous processes either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, biochemical studies have provided novel insights into how bind GPCRs downstream effector proteins. Studies with beta-arrestin mutant mice identified pathophysiological regulated by and/or -2. Following brief summary recent structural studies, this review will primarily focus on beta-arrestin-regulated functions, particular central nervous system roles in carcinogenesis key metabolic including maintenance glucose energy homeostasis. This highlight potential therapeutic implications these discuss strategies could prove useful targeting specific purposes. Significance Statement structurally closely related evolutionarily highly conserved, emerged able vast array outcome cultured cells, complemented structure function, should pave way development classes therapeutically drugs capable regulating

Language: Английский

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Pericytes and the Control of Blood Flow in Brain and Heart

Annual Review of Physiology, Journal Year: 2023, Volume and Issue: 85(1), P. 137 - 164

Published: Feb. 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.

Language: Английский

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

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 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.

Language: Английский

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Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

Cells, Journal Year: 2022, Volume and Issue: 11(5), P. 813 - 813

Published: Feb. 25, 2022

The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between neural cells and blood vessels in human brain, focused mainly on brain gray matter. major components of NVU are neurons, astrocytes (astroglia), microvessels, pericytes, microglia. In addition, we believe oligodendrocytes should also be included as an indispensable component white Of all these components, particular have attracted interest researchers because their unique anatomical location; interposed neurons microvessels brain. Their location suggests might regulate cerebral flow (CBF) response neuronal activity, so ensure adequate supply glucose oxygen meet metabolic demands neurons. fact, adult which accounts for only 2% entire body weight, consumes approximately 20–25% total amount consumed by whole body. needs continuous essential energy sources through CBF, there practically no stores or brain; both acute chronic cessation CBF can adversely affect functions. another important putative function elimination heat waste materials produced activity. Recent evidence play pivotal roles not supplying glucose, but fatty acids amino Loss astrocytic support expected lead malfunction whole, underlies numerous neurological disorders. this review, shall focus historical recent findings with regard contributions NVU.

Language: Английский

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Single Cell Transcriptomic Analysis Reveals Organ Specific Pericyte Markers and Identities

Frontiers in Cardiovascular Medicine, Journal Year: 2022, Volume and Issue: 9

Published: June 1, 2022

Pericytes are mesenchymal-derived mural cells that wrap around capillaries and directly contact endothelial cells. Present throughout the body, including cardiovascular system, pericytes proposed to have multipotent cell-like properties involved in numerous biological processes, regulation of vascular development, maturation, permeability, homeostasis. Despite their physiological importance, functional heterogeneity, differentiation process, pathological roles not yet clearly understood, part due inability reliably distinguish them from other cell populations. Our study focused on identifying pericyte-specific markers by analyzing single-cell RNA sequencing data tissue-specific mouse pericyte populations generated Tabula Muris Senis. We identified cluster murine lung, heart, kidney, bladder expressed either two known markers, Cspg4 or Pdgfrb. further defined as those co-expressed both within this cluster. Single-cell differential expression gene analysis compared subset with clusters potential marker candidates, Kcnk3 (in lung); Rgs4 heart); Myh11 Kcna5 kidney); Pcp4l1 bladder); Higd1b lung heart). In addition, we novel signaling pathways may be maintaining identity. Moreover, were validated Human Lung Cell Atlas human heart RNAseq databases. Intriguingly, found mice conserved pericytes. study, we, for first time, specific among reveal differentially genes relationships between

Language: Английский

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