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Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration [RNAseq-Stroke]

ABSTRACT: Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration [RNAseq-Stroke]

PROVIDER: PRJNA1285181 | ENA |

REPOSITORIES: ENA

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Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration.

Project description:Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration.

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Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration [RNAseq-Stroke]

Project description:We identified the role of brain endothelial cell Hdac2 and Ezh2 mediated epigenetic mechanism in maintaining blood brain barrier in adult mice. Also, we we studied the impact of reactivation of brain endothelial cell Wnt/β-catenin signaling in adult mice. .We evaluated derepression of Hdac2 mediated epigenetic mechanism in imice model of schemic stroke.

2025-07-06 | GSE301448 | GEO

Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuroregeneration.

Project description:We identified the role of brain endothelial cell Hdac2 and Ezh2 mediated epigenetic mechanism in maintaining blood brain barrier in adult mice. Also, we we studied the impact of reactivation of brain endothelial cell Wnt/β-catenin signaling in adult mice.We evaluated derepression of Hdac2 mediated epigenetic mechanism in imice model of schemic stroke.

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Brain pericytes and perivascular fibroblasts are stromal progenitors with dual functions in cerebrovascular regeneration after stroke

Project description:Functional revascularization is key to stroke recovery and requires remodelling of blood vessels, around which is located the brain’s only stromal compartment. Stromal progenitor cells (SPC) form a functional grouping of cells critical for tissue regeneration following injury in many organs, yet their identity in the brain remains elusive despite implications in neovascularization and scar formation. Here we show that the perivascular niche of brain SPCs includes pericytes, venular smooth muscle cells and a distinct population of perivascular fibroblasts, that together help regenerate the cerebral microvasculature following stroke. The ischemic injury triggers amplification of pericytes and perivascular fibroblasts in the infarct region where they associate with endothelial cells inside a reactive astrocyte border. Fate-tracking of Hic1+ SPCs uncovers a transient functional and transcriptional phenotype of stroke-activated pericytes and perivascular fibroblasts, where both populations remain segregated, displaying dichotomous angiogenic and fibrogenic profiles. In the adult brain, pericytes and perivascular fibroblasts are therefore distinct subpopulations of stromal progenitors that coordinate revascularization and scar formation after injury.

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Regulation of Angiogenesis by EZH2

Project description:While VEGF-targeted therapies are showing promise in clinical studies, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homologue 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation and indicates the presence of a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin 1 (VASH1). EZH2 silencing in the tumor-associated endothelial cells resulted in inhibition of angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth. Combined, these data provide a new understanding of the regulation of tumor angiogenesis and support the potential for targeting EZH2 as a novel therapeutic approach. Pre-clinical study, DNA microarray (Illumina HumanHT-12)

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Project description:Blood monocytes/macrophages infiltrate the brain after ischemic stroke and critically influence brain injury and regeneration. We investigated stroke-induced transcriptomic changes of monocytes/macrophages by RNA sequencing profiling, using a mouse model of permanent focal cerebral ischemia. Compared to non-ischemic conditions, brain ischemia induced only moderate genomic changes in blood monocytes, but triggered robust genomic reprogramming in monocytes/macrophages invading the brain. Surprisingly, functional enrichment analysis of the transcriptome of brain macrophages revealed significant overrepresentation of biological processes linked to neurovascular remodeling, such as angiogenesis and axonal regeneration, as early as 5 days after stroke, suggesting a previously underappreciated role for macrophages in initiating post-stroke brain repair. Upstream Regulator analysis predicted peroxisome proliferator-activated receptor gamma (PPARγ) as a master regulator driving the transcriptional reprogramming in post-stroke brain macrophages. Importantly, myeloid cell-specific PPARγ knockout (mKO) mice demonstrated lower post-stroke angiogenesis and neurogenesis than wild-type mice, which correlated significantly with the exacerbation of post-stroke neurological deficits in mKO mice. Collectively, our findings reveal a novel repair-enhancing transcriptome in brain macrophages during post-stroke neurovascular remodeling. As a master switch controlling genomic reprogramming, PPARγ is a rational therapeutic target for promoting and maintaining beneficial macrophage functions, facilitating neurorestoration, and improving long-term functional recovery after ischemic stroke.

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Targeted deletion of astrocytic Nhe1 stimulates Wnt/β-catenin-mediated BBB repair and angiogenesis after ischemic stroke

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Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesiclesAcid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles

Project description:Acid sphingomyelinase (ASM) inhibitors, which are clinically used as anti-depressants for ~60 years, have recently been shown to enhance stroke recovery in rodents. Using mice and cerebral microvascular endothelial cells exposed to ischemia/reperfusion (I/R) we show that the antidepressants amitriptyline, fluoxetine and desipramine induce angiogenesis in an ASM-dependent way by releasing small extracellular vesicles (sEVs) from endothelial cells, which have bona fide characteristics of exosomes and which, similar to sEVs released during I/R, promote angiogenesis. Post-I/R, ASM inhibition elicits a profound brain remodeling response with increased blood-brain barrier integrity, reduced brain leukocyte infiltrates and increased neuronal survival. The ASM inhibitor-mediated release of sEVs has disclosed an elegant target, via which stroke recovery can be amplified. Key words: Antidepressant, ceramide, exosome, focal cerebral ischemia, middle cerebral artery occlusion, sphingomyelin, stroke recovery

2022-10-14 | PXD024106 | Pride

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