A molecular atlas of cell types and zonation in the brain vasculature
Open accessAbstract
Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.
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Many of these transcription factors were well documented.
“many of which were well documented61–66.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [64]
Endothelial independent components had strong contributions from genes with arterial and veinous expression, suggesting heterogeneity related to vessel type.
“We identified endothelial ICs (Figure 2E) with strong contributions from genes with arterial (IC 5 and 20) and veinous (IC 3 and 12) expression, suggesting heterogeneity related to vessel type”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Vanlandewijck et al., 2018
These arterial/veinous genes showed continuous, reciprocal expression, consistent with smooth molecular transitions described for endothelial cells associated with arteries or veins.
“These genes (e.g. Tm4sf1 and Slc38a5) showed continuous, reciprocal expression (Data S4G), consistent with the smooth molecular transitions described for endothelial cells associated with arteries or veins”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Vanlandewijck et al., 2018
IC 19 represented the veinous-arterial difference in a graded rather than categorical way, as Rgs5/Acta2 expression and IC cell scores were continuously distributed across these cells.
“IC 19 represented this difference in a graded rather than categorical way, as Rgs5/Acta2 expression and IC cell scores were continuously, rather than bimodally, distributed across these cells”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Vanlandewijck et al., 2018
Among smooth muscle alpha actin cells, Acta2 expression correlates with a veinous versus arterial distribution.
“Among SMA cells, Acta2 expression correlates with a veinous versus arterial distribution”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Vanlandewijck et al., 2018
A single independent component, IC 13, appeared to encode the distinction between pericytes and smooth muscle alpha actin cells, with pericyte marker Vtn as the strongest loading gene.
“A single IC (IC 13) appeared to encode this distinction, with pericyte marker Vtn as the strongest loading gene”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Vanlandewijck et al., 2018
We observed distinct endothelial cell types carrying known arterial (e.g., Bmx; VECA) and venous (Slc38a5; VECV) markers, as well as capillary endothelial cells (VECC) expressing Meox1.
“Like Vanlandewijck et al., we observed (Figure 5) distinct endothelial cell types carrying known arterial (e.g., Bmx; VECA) and venous (Slc38a5; VECV) markers, as well as capillary endothelial cells (VECC) expressing Meox1.”
From Molecular Architecture of the Mouse Nervous System (2018) · cites this paper as Vanlandewijck et al., 2018
Vanlandewijck et al. described two brain fibroblast-like cell types expressing fibril-forming collagens, collagen fiber crosslinking proteins, and Pdgfra, interposed between astrocyte endfeet and vascular endothelial cells.
“Vanlandewijck et al. described two brain fibroblast-like cell types expressing fibril-forming collagens (e.g., Col1a1, Col1a2), collagen fiber crosslinking proteins (Lum, Dcn), and the platelet-derived growth factor receptor alpha, Pdgfra, which was interposed between astrocyte endfeet and vascular endothelial cells.”
From Molecular Architecture of the Mouse Nervous System (2018) · cites this paper as Vanlandewijck et al., 2018
In vivo, αSMA and calponin expression are restricted to mural cells along brain arterioles and arteries, but these markers are often upregulated during culture, complicating identification of pericytes.
“In vivo, αSMA and calponin expression are restricted to mural cells along brain arterioles and arteries [38], however, these markers are often upregulated during culture [39], complicating identification of pericytes.”
From Role of iPSC-derived pericytes on barrier function of iPSC-derived brain microvascular endothelial cells in 2D and 3D (2019) · cites this paper as [38]
APOE in the brain is primarily synthesized by astrocytes and microglia, as indicated by a recent single cell RNA-seq study in the mouse.
“APOE in the brain is primarily synthesized by astrocytes and microglia, as indicated by a recent single cell RNA-seq study in the mouse (610).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [610]
Pericytes, SMCs, and endothelial cells express thousands of transcripts encoding different transporters, receptors, active efflux pumps, ion channels, and regulatory molecules, whose expression pattern varies by zonation along the arteriocapillary-venous axis and cell type.
“Pericytes, SMCs, and endothelial cells express thousands of transcripts encoding different transporters, receptors, active efflux pumps, ion channels, and regulatory molecules (28, 72, 86, 129, 242, 358, 359, 610, 675, 678), whose expression pattern varies by zonation along the arteriocapillary-venous axis and cell type (610).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [610]
In contrast to the BBB endothelium's gradual phenotypic change along the arteriovenous axis, mural cells formed two distinct groups comprising pericyte and venous SMCs, and arterial and arteriole SMCs.
“In contrast to the BBB endothelium's gradual phenotypic change along the arteriovenous axis, mural cells formed two distinct groups comprising pericyte and venous SMCs, and arterial and arteriole SMCs (610).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [610]
At the BBB endothelium, transcription factors predominated at arteries and arterioles, transporters predominated capillaries and veins, and ribosomal proteins indicative of protein synthesis were spread along the arteriovenous axis.
“Briefly, this study is the first to report that at the BBB endothelium transcription factors predominated at arteries and arterioles, transporters predominated capillaries and veins, and ribosomal proteins indicative of protein synthesis were spread along the arteriovenous axis (610), yielding important insights to biological functions and endothelial specialization along the brain vasculature”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [610]
Plcg2 is expressed in certain subtypes of endothelial cells, although at lower level than in microglia.
“According to a transcriptomic analysis of cells in the vasculature, Plcg2 seems to be expressed in certain subtypes of endothelial cells, although at lower level than compared to microglia (http://betsholtzlab.org/VascularSingleCells/database.html [43]).”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [43]
Ppib is abundantly and ubiquitously expressed across CNS cell types.
“we used an siRNA sequence targeting Ppib because this gene is abundantly and ubiquitously expressed across CNS cell types [27].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [27]
Ppib is abundantly and ubiquitously expressed across CNS cell types.
“Here, we used an siRNA sequence targeting Ppib because this gene is abundantly and ubiquitously expressed across CNS cell types.34”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [34]
WAVE2 is expressed at high levels in microglia and vascular endothelial cells.
“WAVE2 is expressed at high levels in microglia and vascular endothelial cells14,15.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [14]
PDGFRβ expression is higher in pericytes than in smooth muscle cells.
“PDGFRβ expression in pericytes is noticeably higher than in SMCs18,25,26.”
From Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction (2019) · cites this paper as [25]
Endo.1 may correspond to endothelial capillary cells, Endo.2 to venous endothelial cells, and Endo.3 to arterial endothelial cells.
“Based on marker gene enrichment (Table S1), Endo.1 may correspond to endothelial capillary cells, Endo.2 to venous endothelial cells, and Endo.3 to arterial endothelial cells (Vanlandewijck et al., 2018).”
From Single-Cell Analysis of Regional Differences in Adult V-SVZ Neural Stem Cell Lineages (2019) · cites this paper as Vanlandewijck et al., 2018
Spatially mapped the developing arterio-venous zonation in the embryonic LV ChP in whole explants.
“We spatially mapped the developing arterio-venous zonation in the embryonic LV ChP in whole explants by combining the pan-endothelial marker PECAM1 with markers for arteries (Acta2+, Vwf+) and veins (Acta2−, Vwf+) (Vanlandewijck et al., 2018).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Vanlandewijck et al., 2018
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Self-citationPreparation of single cell suspensions from the adult mouse lung
Vanlandewijck, M., Vanlandewijck, M., Andræ, J., et al. (2018) · Protocol Exchange · doi:10.1038/protex.2018.006 · Cited by 3 · see citing works
Self-citationIsolation of vessel-associated pdgfra-H2BGFP positive cells from murine brain
Vanlandewijck, M., Vanlandewijck, M., Andræ, J., et al. (2018) · Protocol Exchange · doi:10.1038/protex.2018.005 · Cited by 1 · see citing works
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Blood-Brain Barrier: From Physiology to Disease and Back
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Cells of the adult human heart
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Molecular diversity and specializations among the cells of the adult mouse brain
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“The first stage of analysis robustly grouped cells into 8–11 broad classes (Data S2), including neurons, astrocytes, microglia/macrophages, oligodendrocytes, polydendrocytes (oligodendrocyte progenitor cells), and components of the vasculature—endothelial cells, fibroblast-like cells, andmural cells (Abbott et al., 20…”
BackgroundResultInfluentialBlood–brain barrier breakdown is an early biomarker of human cognitive dysfunction
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The blood–brain barrier and blood–tumour barrier in brain tumours and metastases
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Single-Cell Transcriptome Atlas of Murine Endothelial Cells
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Strategies for delivering therapeutics across the blood–brain barrier
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The role of brain vasculature in neurodegenerative disorders
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Challenges to curing primary brain tumours
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A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
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Self-citationSingle-cell transcriptomic profiling of the aging mouse brain
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Vascular Cognitive Impairment and Dementia
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The blood–brain barrier in health and disease: Important unanswered questions
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Functional characterization of the dural sinuses as a neuroimmune interface
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“Consistent with previous studies on CNS vasculature (Vanlandewijck et al., 2018), brain stromal sequencing was largely comprised of Pecam1+ endothelial cells with capillary (cECs; Tfrchi), arterial (aECs; Bmxhi), or venous (vECs; Trfclo, Bmxlo, Vwfhi) zonation markers and high expression of…”
InfluentialMuhl, L., Genové, G., Leptidis, S., Liu, J., He, L., Mocci, G., Sun, Y., Gustafsson, S., Buyandelger, B., Chivukula, I. V., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17740-1 · Cited by 668 · see citing works
“8b, c, Supplementary Data 10) and likely represent SMC from the heart ’ s large vessel outlets, i.e., the pulmonary trunk and aorta 49,50 .”
InfluentialSelf-citationRevisiting the neurovascular unit
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The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains
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Molecular architecture of the developing mouse brain
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Notch signalling drives synovial fibroblast identity and arthritis pathology
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Vascular endothelial cell development and diversity
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Development and Cell Biology of the Blood-Brain Barrier
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“While Slc2a1−/− mice die at embryonic stages, mice haploinsufficient for Slc2a1 recapitulate the features seen in human patients (Wang et al. 2006).”
BackgroundNeurovascular and Cognitive Dysfunction in Hypertension
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“Recent single-cell RNA sequencing studies have started to unveil the molecular bases of the diversity of the cellular composition of the cerebrovascular tree.(52) These efforts, still in an initial stage, will provide critical insight into the cellular, molecular, and signaling mechanisms underlying the segmental susc…”
BackgroundPhysiological blood–brain transport is impaired with age by a shift in transcytosis
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Integrated Single-Cell Atlas of Endothelial Cells of the Human Lung
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What is a cell type and how to define it?
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Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
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Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease
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Neuronal regulation of the blood–brain barrier and neurovascular coupling
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Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development
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“SARS-CoV-2 gains cellular entry via its receptors angiotensin-converting enzyme 2 and transmembrane protease serine 2, but it may enter via other receptors, including neuropilin and vimentin, all of which are enriched in cells of the neurovascular unit 6–10 .”
Drug delivery to the central nervous system
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Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types
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Self-citationPericytes and Neurovascular Function in the Healthy and Diseased Brain
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Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells
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Brain capillary pericytes exert a substantial but slow influence on blood flow
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Single-cell spatial immune landscapes of primary and metastatic brain tumours
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Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss
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“In contrast to our present findings and findings by others 5,24,39 , another recent single cell transcriptome study using wild type mice suggested that other CNS cell types, as for example arterial endothelial cells express high levels of Ptn 46 .”
InfluentialHigh-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle-Resident Cell Populations
Giordani, L., He, G. J., Négroni, E., Sakai, H., Law, J. Y. C., Siu, M. M., Wan, R., Corneau, A., Tajbakhsh, S., Cheung, T. H., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.026 · Cited by 389 · see citing works
Mapping the Fine-Scale Organization and Plasticity of the Brain Vasculature
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A cellular and spatial map of the choroid plexus across brain ventricles and ages
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Generation of vascularized brain organoids to study neurovascular interactions
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Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression
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“Recent sequencing studies performed in whole mouse and human brains revealed that HDAC2 expression is higher than HDAC1 in endothelial cells (14, 40).”
A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution
Shapson-Coe, A., Januszewski, M., Berger, D. R., Pope, A., Wu, Y., Blakely, T., Schalek, R. L., Li, P. H., Wang, S., Maitin-Shepard, J., et al. (2024) · Science · doi:10.1126/science.adk4858 · Cited by 361 · see citing works
Genetic mapping of cell type specificity for complex traits
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Multisensory gamma stimulation promotes glymphatic clearance of amyloid
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“We further annotated vascular cells as endothelial cells, pericytes, smooth muscle cells and fibroblasts 28 (Fig.”
BackgroundSingle-cell multiregion dissection of Alzheimer’s disease
Mathys, H., Boix, C. A., Akay, L. A., Xia, Z., Davila-Velderrain, J., Ng, A. P., Jiang, X., Abdelhady, G., Galani, K., Mantero, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07606-7 · Cited by 343 · see citing works
“We annotated cell types using previously published marker genes and single-cell RNA-seq data 9,12,33,91–93 .”
A systems view of the vascular endothelium in health and disease
Augustin, H. G., & Koh, G. Y. (2024) · Cell · doi:10.1016/j.cell.2024.07.012 · Cited by 370 · see citing works
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The anatomy and immunology of vasculature in the central nervous system
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A single-cell atlas of the normal and malformed human brain vasculature
Winkler, E. A., Kim, C. N., Ross, J. M., Garcia, J. H., Gil, E., Oh, I., Chen, L. Q., Wu, D., Catapano, J. S., Raygor, K. P., et al. (2022) · Science · doi:10.1126/science.abi7377 · Cited by 324 · see citing works
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“Therefore we and others have extended referring to this vascular segment as BBB (9), as these characteristics impact on immune cell trafficking into the CNS (7, 10, 11).”
BackgroundSingle-cell dissection of the human brain vasculature
García, F., Sun, N., Lee, H., Godlewski, B. R., Mathys, H., Galani, K., Zhou, B., Jiang, X., Ng, A. P., Mantero, J. C., et al. (2022) · Nature · doi:10.1038/s41586-022-04521-7 · Cited by 310 · see citing works
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Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis
Rohlenová, K., Goveia, J., García‐Caballero, M., Subramanian, A., Kalucka, J. M., Treps, L., Falkenberg, K. D., de Rooij, L. P. M. H., Zheng, Y., Lin, L., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.009 · Cited by 309 · see citing works
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
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“The mechanism underlying the difference is unclear but possibly related to the differential APOE receptor expression [295, 296], or isoform-specific impact on different vascular cell types [140, 297].”
BackgroundMicroglial metabolic flexibility supports immune surveillance of the brain parenchyma
Bernier, L., York, E. M., Kamyabi, A., Choi, H. B., Weilinger, N. L., & MacVicar, B. A. (2020) · Nature Communications · doi:10.1038/s41467-020-15267-z · Cited by 302 · see citing works
Single-cell RNA-seq reveals the transcriptional landscape in ischemic stroke
Zheng, K., Lin, L., Jiang, W., Chen, L., Zhang, X., Zhang, Q., Ren, Y., & Hao, J. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x211026770 · Cited by 306 · see citing works
“We found six vascular endothelial cells (ECs) subclusters (Figure S10(a)) according to the established markers of ECs in previous studies.(44,45) Ischemia-induced inflammation and oxidative stress increased endothelial cell death, which directly resulted in the decrease of the cell percentage in the MCAO group, while,…”
BackgroundResultSpecification of CNS macrophage subsets occurs postnatally in defined niches
Masuda, T., Amann, L., Monaco, G., Sankowski, R., Staszewski, O., Krueger, M., Del Gaudio, F., He, L., Paterson, N., Nent, E., et al. (2022) · Nature · doi:10.1038/s41586-022-04596-2 · Cited by 294 · see citing works
Self-citationEndothelial heterogeneity across distinct vascular beds during homeostasis and inflammation
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Epigenetic Modifications in Cardiovascular Aging and Diseases
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“etic enzymes/pathways in specific diseased cohorts or cell types.(54,57,58,146) Altogether, new sequencing technologies have”
BackgroundImmunometabolism in the Brain: How Metabolism Shapes Microglial Function
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Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord
Milich, L. M., Choi, J. S., Ryan, C. B., Cerqueira, S. R., Benavides, S., Yahn, S. L., Tsoulfas, P., & Lee, J. K. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20210040 · Cited by 285 · see citing works
A connectomic study of a petascale fragment of human cerebral cortex
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“Separation of smooth muscle cells from pericytes was possible in arteries and arterioles, however not clear in veins and venules as predicted by the expression profiles of these cells (Vanlandewijck et al. 2018).”
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InfluentialBrain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues
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Advances in Understanding the Pathophysiology of Lacunar Stroke
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Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential
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“The second blood endothelial cell cluster, termed BEC, includes a heterogeneous set of non-HEV endothelial cells, including arterial, capillary, and non-HEV venular cells (Figures S5H and S5I; Vanlandewijck et al., 2018).”
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Contractile pericytes determine the direction of blood flow at capillary junctions
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Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants
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- Authors
- Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., Sun, Y., Raschperger, E., Räsänen, M., Zarb, Y., Mochizuki, N., Keller, A., Lendahl, U., & Betsholtz, C.
- Affiliations
- Uppsala University (SE)
- Tianjin Medical University General Hospital (CN)
- Karolinska Institutet (SE)
- University of Zurich (CH)
- Japan Agency for Medical Research and Development (JP)
- Corresponding author
- Betsholtz, Christer
- ORCID
- Venue
- Nature
- Published
- 2018-02-14
- Volume
- 554
- Issue
- 7693
- Pages
- 475-480
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2786318872
- Semantic Scholar
- 237e37a314d2faef1d389b147614e8fa550a3087
- Cited by
- 2,074
- References
- 65
- Citations by year
- 2026: 169 · 2025: 246 · 2024: 271 · 2023: 240 · 2022: 268 · 2021: 274 · 2020: 224 · 2019: 130 · 2018: 65
- FWCI
- 69.29
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-06-20)
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- cerebral vasculature, blood-brain barrier, endothelial cells, mural cells, pericytes, smooth muscle cells, perivascular cells, single-cell transcriptomics
- MeSH terms
- Animals, Arteries, Arterioles, Blood Vessels, Brain, Capillaries
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