Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration following stroke

ABSTRACT: Neutralizing factors involved in blood vessel dysfunction offer a promising strategy for stroke recovery. Many extracellular proteins need enzymatic activation to function, and blocking this activation is an untapped approach to restoring vessel integrity. Here, we demonstrate that inhibition of the extracellular protease SKI-1 with PF-429242 restores blood-vessel integrity and promotes functional recovery in both large- and small-animal models for stroke. Single-cell mRNA sequencing identified molecular signatures suggesting that PF-429242 restores the expression of genes involved in vessel integrity in endothelial cells. Moreover, we identify a mechanism whereby RGMa cleavage by SKI-1 is required for RGMa to interact with Neogenin and alter vessel integrity. Either preventing RGMa cleavage or deleting Neogenin on endothelial cells reduced blood vessel dysfunction, increased tissue preservation, and restored brain function following stroke. This work identifies a much-needed therapeutic strategy which restores blood vessel integrity and functionality, showing efficacy in small- and large-animals.

ORGANISM(S): Mus musculus

PROVIDER: GSE300442 | GEO | 2025/07/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration following stroke

Project description:Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration following stroke

| PRJNA1280962 | ENA

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

Zebrafish functional xenograft vasculature platform identifies PF-502 as a durable vasculature normalization drug

Project description:Tumor vasculature are structurally chaotic and functionally inefficient. Restoring aberrant tumor blood vessels, or “normalize” the tumor vasculature can alleviate hypoxia and enhance intra-tumoral drug delivery. However, identifying tumor vascular normalizing drugs are currently hampered by an absence of efficient screening platform. We aimed to develop a robust method to visualize, digitalize and evaluate the structural and functional changes of tumor vasculature in batch: zebrafish functional xenograft vasculature platform (zFXVP). As proof of principle, we applied zFXVP to a small compound library which has been implicated in affecting the morphology of tumor vasculature. zFXVP identified PF-502 as a durable tumor vascular normalization agent. Further molecular analysis using RNA-Seq, pharmaceutical inhibition and gene knockout indicate PF-502 can induce endothelial cell cycle arrest and simplify redundant tumor vasculature by blocking PI3K/mTOR signaling and stabilize the vessel lumen and stimulate the blood function by activating Notch1 signaling with mediating S3 cleavage. Last, in mouse tumor xenograft model, PF-502 reproduced a potent vascular normalizing effect at a sub MTD (maximum tolerated dose) and showed its ability to improve intra-tumoral drug delivery and synergize chemotherapy, which confirms the reliability of zFXVP and implicates the potential application of PF-502 in clinical practice as an adjuvant vascular normalization drug.

2023-09-13 | GSE224106 | GEO

Differentiation of Mammary Tumors by SKI-606 (bostutinib) (gene expression)

Project description:While c-Src is infrequently mutated in human cancers, it mediates oncogenic signals of many activated growth factor receptors and thus remains a key potential target of cancer therapy. However, the widespread function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune competent environment. In an effort to direct clinical use of Src inhibitors, we tested the effectiveness of one of the four Src inhibitors in clinical testing, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model. Here we show that oral administration of the Src inhibitor SKI-606 inhibited the phosphorylation of Src in mammary tumors, and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in more than half of the animals treated from puberty and stopped tumor growth in older animals with preexisting tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors in this model by inducing differentiation. Differentiation of Mammary Tumors by SKI-606 (bostutinib)

2011-01-01 | E-GEOD-22150 | biostudies-arrayexpress

Differentiation of Mammary Tumors by SKI-606 (bostutinib) (illumina)

2010-09-15 | E-GEOD-20921 | biostudies-arrayexpress

Gene expression changes in brain vascularture in Notch3 knockout mice

Project description:Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the progressive loss of VSMC in the Notch3-/- mouse on blood vessel integrity in the central nervous system To explore the molecular consequences of the VSMC phenotype in Notch3-/- mice, we performed genome-wide transcriptional profiling of the brain vasculature in mutants and littermate controls using Affymetrix Mouse Genome 430 2.0 Array.

2015-02-18 | GSE55203 | GEO

Repair-Associated Macrophages Increase after Early-phase Microglia Attenuation to Promote Ischemic Stroke Recovery [scRNA-Seq]

Project description:Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.

2025-02-21 | GSE290194 | GEO

Repair-Associated Macrophages Increase after Early-phase Microglia Attenuation to Promote Ischemic Stroke Recovery [RNA-Seq]

2025-02-21 | GSE290191 | GEO

Glycogen stress granules cause astrocytic mitochondrial dysfunction to aggravate ischemic damage and delay recovery after stroke

Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We reveal that glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery. Our work identifies glycogen stress granules as pathogenic signaling hubs linking astrocytic metabolic stress to mitochondrial failure through compartmentalized HDAC3-ATAD3A crosstalk, and proposes a dual-target paradigm addressing both substrate overload and protein acetylation dynamics for stroke neurorestoration.

2025-05-10 | GSE295882 | GEO

Blockade of VCAM1 or VLA4 preserves cerebrovasculature and prevents cognitive decline late after stroke

Project description:Infarct-induced neurodegeneration increases dementia risk for at least a decade in humans. It can be modeled in wildtype mice, where a cortical stroke results in chronic lymphocytic infiltration into the infarct and delayed cognitive decline. Vascular cell adhesion molecule 1 (VCAM1) on endothelial cells is increased by stroke and facilitates immune cell diapedesis by binding very late antigen 4 (VLA4) on immune cells. We report here that after stroke, chronic but not acute treatment with an anti-VCAM1 blocking antibody reduces B and T lymphocyte infiltration and prevents chronic cognitive dysfunction in wildtype male and female mice. Preservation of cognitive function was also seen with chronic anti-VLA4 treatment despite anti-VLA4’s lack of effect on lymphocyte infiltration. High-depth single-cell RNA sequencing of the chronic infarct and peri-infarct cortex revealed a pronounced decrease in expression of blood vessel growth and maturation genes in endothelial cells that was reversed by both anti-VLA4 and anti-VCAM1. Plasma proteomics also support a vasculoprotective mechanism of anti-VCAM1. Finally, immunostaining demonstrated that both antibodies improve pericyte coverage of the vasculature and prevent extravascular fibrinogen leakage. Together, our findings indicate that vascular structure and function remain abnormal long after stroke and that the VLA4/VCAM1 axis is a promising treatment target for infarct-induced neurodegeneration as blockade restores cerebrovasculature and prevents cognitive decline.

2025-06-25 | GSE300564 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data