The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling
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ABSTRACT:
PROVIDER: PRJNA1105051 | ENA |
REPOSITORIES: ENA
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Project description:Stroke is a leading cause of death and long-term disability. In up to 30% of cases the underlying etiology is cerebral small vessel disease (SVD), the mechanisms of which are insufficiently understood. Genome-wide association studies have identified FOXF2 as a major risk gene for SVD and stroke. Foxf2 encodes a transcription factor that in the brain is primarily expressed in endothelial cells (ECs) and pericytes but the mechanisms linking Foxf2 to cerebrovascular disease are unknown. Here we show that Foxf2 maintains EC function via Tie2 signaling and limits infarct size in mice after middle cerebral artery occlusion. EC-specific inactivation of Foxf2 in adult mice resulted in blood-brain barrier leakage, which was exacerbated after experimental stroke compared to controls. Proteomic analyses of brain ECs from Foxf2 deficient mice as well as human pluripotent stem cell (iPSC) derived ECs lacking FOXF2 revealed a downregulation of multiple proteins involved in Tie2 signaling. We further found that endothelial Foxf2 deficiency compromises functional hyperemia, reduces endothelial NO production, and increases the size of experimentally induced infarcts via Tie2 signaling. Pharmacological treatment with the Tie2 activator AKB-9778 rescued the effects of Foxf2 deficiency on key outcomes. Moreover, RNA sequencing in combination with chromatin immunoprecipitation sequencing (ChIP-seq) in ECs revealed that FOXF2 functions as a transcriptional activator of Tie2 and other endothelial lineage-specific genes. Collectively, our results highlight the role of endothelial dysfunction and of reduced Tie2 signaling in SVD and stroke, thus offering new perspectives for therapeutic interventions.
2025-04-26 | GSE265959 | GEO
Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard. Microarray analysis in peripheral blood cells includes eight patients with AF and stroke and eight AF subjects without stroke
2016-04-01 | E-GEOD-66724 | biostudies-arrayexpress
Project description:To identify the genes and pathways regulated by FOXF2, we investigated potential FOXF2 gene targets by microarray analyses of primary prostate stromal cells (PrSC) in which FOXF2 was knocked down by siRNA. 190 differentially expressed genes were selected, of which 104 genes were more highly expressed in PrSC cells treated with FOXF2 siRNA and 86 were more highly expressed in PRSC cells treated with negative control siRNA. Experiment Overall Design: In each experiment, we compared gene expression of PrSC cells treated with FOXF2 siRNA versus PrSC cells treated with negative control siRNA, in a total of 6 affymetrix arrays. 190 differentially expressed genes were selected (ratio negative control siRNA/siRNA ⥠2log |0.8| as average in all arrays).
2008-11-13 | E-GEOD-12444 | biostudies-arrayexpress
Project description:Serum miRNA-based risk prediction for stroke
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Project description:Brain of the foxf2 mutant mouse embryo shows microvascular aneurysm, underdeveloped blood brain barrier and also significant defects in the tissue integrity. Foxf2 expresses in the pericytes of the brain and seem to play an important role in proper development of the BBB. Brains of E18.5 wt and foxf2 mutant mouse embryos dissected and RNA extracted from the brains using Sigma mammalian total RNA extraction kit. The RNA then been sent to th core facility for hybridization.
2015-03-02 | E-GEOD-54531 | biostudies-arrayexpress
Project description:To identify the genes and pathways regulated by FOXF2, we investigated potential FOXF2 gene targets by microarray analyses of primary prostate stromal cells (PrSC) in which FOXF2 was knocked down by siRNA. 190 differentially expressed genes were selected, of which 104 genes were more highly expressed in PrSC cells treated with FOXF2 siRNA and 86 were more highly expressed in PRSC cells treated with negative control siRNA.
2008-11-01 | GSE12444 | GEO
Project description:Cleft palate is among the most common structural birth defects in humans. Previous studies have shown that mutations in FOXF2 are associated with cleft palate in humans and mice and that Foxf2 acts in a Shh-Foxf-Fgf18-Shh molecular network controlling palatal shelf growth. In this study, we generated mice carrying 3xFLAG epitope-tagged endogenous Foxf2 protein using the CRISPR/Cas9-mediated genome editing technology and characterized genome-wide Foxf2 binding sites in the developing palatal shelves using chromatin immunoprecipitation and genome sequencing (ChIP-seq). By combined analysis of ChIP-seq and RNA-seq datasets we identified a large list of Foxf2 target genes. Further analyses demonstrate that Foxf2 directly regulate expression of several genes encoding ECM or ECM modifiers during palate development. Moreover, our ChIP-seq and RNA-seq datasets provide an excellent resource for comprehensive understanding of the molecular network controlling palate development.
2020-02-11 | GSE137585 | GEO
Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard.
2016-04-01 | GSE66724 | GEO
Project description:This genome-wide gene expression studies are aimed at deciphering whether FOXF2 transcriptional activity and specificity are compromised in FOXF2-expressing breast cancer cells (MDA-MB-231) compared with FOXF2-expressing normal breast epithelial cells (MCF10A).
2017-07-31 | GSE55675 | GEO
Project description:We performed single cell RNA-Seq of FACS-isolated CD45+ leukocytes and Lin-CD24- prostate stromal cells from Col1a2-TRAMP(Control) group and Col1a2-Foxf2-TRAMP group. Unsupervised clustering analysis on integrated single-cell datasets revealed an increased CD8+ T cell frequency and activity and a decreased Macrophage and MDSC activity in the Col1a2-Foxf2-TRAMP mice. The analysis in TRAMP mice revealed two major subpopulations that represented the myofibroblastic CAF (myCAF) and inflammatory CAF (iCAF). The percentage of myCAF increased by 15% in the Col1a2-Foxf2-TRAMP mice, suggesting that Foxf2 induced a shift toward the myCAF phenotype. On the other hand, the overall CAF gene signature score defined by the average expression of 30 CAF-associated genes on a single cell level was slightly but significantly reduced in the Col1a2-Foxf2-TRAMP mice.
2022-10-20 | GSE193280 | GEO