Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Microarray data from control and pericyte-deficient mouse brain microvascular transcriptomes

ABSTRACT: The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).

ORGANISM(S): Mus musculus

SUBMITTER: Bengt Johansson

PROVIDER: E-GEOD-15892 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Pericytes regulate the blood-brain barrier.

Armulik Annika A Genové Guillem G Mäe Maarja M Nisancioglu Maya H MH Wallgard Elisabet E Niaudet Colin C He Liqun L Norlin Jenny J Lindblom Per P Strittmatter Karin K Johansson Bengt R BR Betsholtz Christer C

Nature 20101013 7323

The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these differe ...[more]

PMID: 20944627

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Project description:The blood brain barrier (BBB) acts both a physical as well as a metabolic barrier isolating the Central Nervous System (CNS) from systemic circulation, blocking intravascular toxin entry and promoting toxic substance elimination to blood stream. The BBB is formed by four main cellular elements: endothelial cells, astrocyte end-feet, microglial cells, and pericytes. There is strong evidence that astrocytes are able to regulate the phenotypes of endothelial cells by directly contacting or secreting a range of chemical agents, resulting in BBB permeability changes and so on. Conversely, endothelium-derived leukemia inhibitory factor (LIF) has been shown to induce astrocytic differentiation, from studies in normal condition of cell culture. However, in pathological conditions, the specific regulatory mechanism that endothelial cells exert on astrocytes is still less known. In our recently study, a transwell-based, endothelial-astrocyte co-culture model was established to investigate this regulatory relationship in bacterial infection. An extraintestinal pathogenic Escherichia. coli strain was used to infect human brain microvascular endothelial cells (hBMEC) planted in the upper chamber, astrocytes co-cultured in the bottom well were actived without direct contact with bacteria or endothelial cell. The transcription levels of some chemokines and cytokines such as TNF-α and CXCL10 were significantly upregulated. We hypothesized that the secreted proteins from endothelial cells is the main cause of astrocyte activation and the culture supernatant of hBMEC infected by E.coli was obtained to perform the mass spectrometry analysis. In summary, the proteomic identification results showed that 2,692 common proteins were identified in the two groups of control and infected hBMEC, including 140 differentially expressed proteins. The bioinformatics analysis indicated that differentially expressed proteins are mainly classified into structural molecular activity and constituent of ribosome. KEGG pathway enrichment analysis showed that many proteins are involved in focal adhesion as well as a bunch of signaling pathways, PI3K-Akt, Rap1, Ras, MAPK and NF-kappaB signaling pathways, for example. The present study laid an important foundation for the subsequent study of secreted proteins of hBMEC in bacterial infections.

Project description:Genetic variation in the population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited correlation with human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain – the blood-brain barrier (BBB) serves as a major obstacle for CNS drug delivery. Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the intact BBB in different inbred mouse strains.We investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions – cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus. We did not detect differences in cortical and hippocampal vessel density and pericyte coverage among all the investigated strains. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. Our analysis shows that although there were no major differences in parenchymal vascular morphology and BBB permeability between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.

Dataset Information

Microarray data from control and pericyte-deficient mouse brain microvascular transcriptomes

Publications

Pericytes regulate the blood-brain barrier.

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