Transcription profiling of mouse microvascular transcriptomes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Liqun He
PROVIDER: E-GEOD-9202 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Little is known about the pan-microvascular transcriptome, particularly considering gene transcripts and their encoded proteins that can be considered as vascular-selective in their expression. Using a combination of publicly available and our own transcript profiles, we identified a core set of gene transcripts, which are specifically and broadly expressed in the microvasculature. Keywords: cell type comparison, developmental regulation
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Project description:The microvasculature plays a key role in tissue perfusion, transport of mediators, and exchange of gases and metabolites to and from tissues. Microvascular dysfunction has emerged as an important contributor to cardiovascular diseases. In this study we used human blood vessel organoids (BVOs) as a model of the microvasculature to delineate the mechanisms of microvascular dysfunction caused by metabolic rewiring. BVOs fully recapitulated key features of the normal human microvasculature, including reliance of mature endothelial cells (ECs) on glycolytic metabolism, as concluded from metabolic flux assays using 13C-glucose labelling and mass spectrometry-based metabolomics. Pharmacological targeting of PFKFB3, a potent activator of glycolysis, with two different chemical inhibitors resulted in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also displayed similar structural remodelling compared to control BVOs. Proteomic analysis of the BVO secretome revealed remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovered tight junction formation and increased pericyte coverage in microvessels. Our metabolic and proteomics findings demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.
2023-09-13 | PXD041780 | Pride
Project description:The placental microvasculature of the human fetus is essential for the efficient transfer of gases, nutrients and waste between the mother and fetus. Microvascular hypoplasia of the terminal villi is associated with the placental pathology observed in cases of severe Intra Uterine Growth Restriction (IUGR). We used novel methods to isolate a pure population of placental microvascular endothelial cells from control preterm placentas (n=3) and placenta complicated by severe IUGR (n=6) with superimposed preeclampsia (n=5). Distal placental villous tissue was collected to enrich for terminal villi. Tissue was minced, digested and placental microvascular endothelial cells (PlMEC) were positively selected using tocosylated magnetic Dynabeads labeled with Human Endothelial Antigen lectin. The purity of the PlMEC (95%) was assessed by CD31 immunocytochemistry. RNA was extracted from the PlMEC samples and also from 3 term placenta and subjected to Affymetrix microarray analysis (U133Plus2 array chips). Data from the 3 term placentas and 3 preterm PlMEC arrays was used to generate an endothelial cell specific gene profile. This profile was used to identify the endothelial genes differentially regulated in all 6 IUGR cases. BTNL9 and NTRK2 transcripts were upregulated and SAA1, GNAS and SLAMF1 transcripts were downregulated as relative to the preterm controls. These changes were validated by Real time PCR in the PlMEC samples. This novel study is the first to identify endothelial candidate genes that may play a role in the villous hypoplasia of severe IUGR. This work advances our understanding of the molecular defects in placental microvascular endothelial cells in normal and pathologic pregnancies.
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Project description:Aims: The microcirculation serves crucial functions in adult heart, distinct from those carried out by epicardial vessels. Microvessels are governed by unique regulatory mechanisms, impairment of which leads to microvessel-specific pathology. There are few treatment options for patients with microvascular heart disease, primarily due to limited understanding of underlying pathology. We developed an integrated process for simultaneous isolation and culture of the main cell types comprising the microcirculation in adult mouse heart: endothelial cells, pericytes and vascular smooth muscle cells, and here we characterize the transcriptional profile of each cell type. Methods and Results: Confluent cultures of mouse cardiac endothelial cells, pericytes and vascular smooth muscle cells underwent transcriptional profiling using RNA sequencing. We define the top 50 transcripts expressed by each cell type. Conclusions: We define microvascular cell transcriptional profiles, identify novel transcripts, and confirm established cell-specific markers. Our results allow identification of unique markers and regulatory transcripts that govern microvascular physiology and pathology.
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Project description:Purpose: Pericytes, the mural cells of blood microvessels, have come into focus as regulators of microvascular development and function, but due to paucity of defining markers, the identification and functional characterization of PC remain problematic, and reported data are often controversial. Here, we used a new approach for the isolation of mural cell from mouse brain in combination with RNA-sequencing (RNA-seq) and previously published vascular transcriptome data to assemble a state-of-the-art catalogue of brain mural cell-enriched gene transcripts. Methods: We isolated double positive cells from the brain of Pdgfrb-eGFP/NG2-DsRed transgenic mice using FACS. Cells were lysed, RNA extracted and sequenced with next-generation sequencing (NGS). For comparison, we also determined the transcriptome of brain microvascular fragments (containing both endothelial cells and mural cells) isolated by mechanical tissue disintegration, collagenase digestion and immune-panning using anti-CD31 antibodies coupled to magnetic beads. The reads were aligned to the Ensembl mouse gene assembly (NCBIM37) using Tophat2 software (version 2.0.4). The duplicated reads were removed using the picard tool (version 1.92). To identify the genes significantly enriched in the pericyte samples as compared with microvascular samples, statistical tests were performed using the Cufflinks tool (version 2.2.1) Results: The result showed that mRNA transcripts representing 856 different genes were enriched more than two-fold in FACS isolated Pdgfrb-eGFP/NG2-DsRed double positive cells compared with whole microvascular fragments (False Discovery Rate < 0.05) The RNA from three FACS sorted brain mural cell samples and three whole brain microvascular samples isolated from three animals were processed and sequenced on the Illumina HiSeq 2500 platform in the sequencing facility in Uppsala University.
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Project description: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).
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Project description:Purpose: Pericytes, the mural cells of blood microvessels, have come into focus as regulators of microvascular development and function, but due to paucity of defining markers, the identification and functional characterization of PC remain problematic, and reported data are often controversial. Here, we used a new approach for the isolation of mural cell from mouse brain in combination with RNA-sequencing (RNA-seq) and previously published vascular transcriptome data to assemble a state-of-the-art catalogue of brain mural cell-enriched gene transcripts. Methods: We isolated double positive cells from the brain of Pdgfrb-eGFP/NG2-DsRed transgenic mice using FACS. Cells were lysed, RNA extracted and sequenced with next-generation sequencing (NGS). For comparison, we also determined the transcriptome of brain microvascular fragments (containing both endothelial cells and mural cells) isolated by mechanical tissue disintegration, collagenase digestion and immune-panning using anti-CD31 antibodies coupled to magnetic beads. The reads were aligned to the Ensembl mouse gene assembly (NCBIM37) using Tophat2 software (version 2.0.4). The duplicated reads were removed using the picard tool (version 1.92). To identify the genes significantly enriched in the pericyte samples as compared with microvascular samples, statistical tests were performed using the Cufflinks tool (version 2.2.1) Results: The result showed that mRNA transcripts representing 856 different genes were enriched more than two-fold in FACS isolated Pdgfrb-eGFP/NG2-DsRed double positive cells compared with whole microvascular fragments (False Discovery Rate < 0.05)
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