Fibronectin mediates the interaction between vascular pathology and Alzheimer’s disease by inhibiting homeostatic gliovascular crosstalk
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE268780 | GEO | 2026/07/02
REPOSITORIES: GEO
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Project description:Alzheimer's disease (AD) frequently occurs alongside cerebrovascular pathology (CVP), which together exacerbate cognitive decline and dementia. Gaining insights into the molecular interactions between these conditions is crucial for creating effective treatments that can tackle the complexities of AD. To determine impact of gliovascular interactions on the blood-brain-barrier (BBB) experimentally, we utilized a well-established zebrafish model.We treated double transgenic (Tg(fli1a:eGFP)/Tg(her4.1:dRFP)) zebrafish with vegf receptor inhibitor cocktails to evaluate the BBB integrity. By blocking VEGF signaling we showed that astroglial-endothelial interactions are essential for BBB integrity.
2026-07-02 | GSE269111 | GEO
Project description:Growing evidence implicates dysfunctional brain vasculature occurring early in Alzheimer’s disease (AD) progression. Few studies have attempted to bridge transcriptomic signatures with early neuroimaging observations of vascular abnormalities. We leveraged longitudinal in vivo imaging of the cerebrovascular tree in APP/PS1 mice to identify when vascular abnormalities emerge, followed by bulk RNA-seq of isolated brain vessels at this time point. At 9–11 months of age, AD mice exhibited microvascular remodeling and dysfunction, including increased tortuosity, decreased capillary blood flow and reduced vascular density. Enriched gene pathways highlighted increased neuroinflammation, dysfunctional angiogenesis, and deficits in actin-mediated muscle contractility. Mapping transcriptional changes to a mouse vascular atlas implicated endothelial cells and microglia in impaired angiogenesis, while mural cells showed actin-filament and ion channel deficits. Mapping to a human vascular atlas identified translational targets to alleviate actin-mediated contractility deficits. Our integrated framework advances cerebrovascular biomarker understanding and informs early-stage AD therapeutic targets.
2026-03-13 | GSE291921 | GEO
Project description:The invasive and metastatic spread of ovarian cancer (OC) results from the cooperative interactions between cancer and stroma, which include acellular extracellular matrix (ECM) and cellular components, such as cancer-associated fibroblasts (CAFs). Soluble growth factors secreted by cancer and stromal cells contribute to stroma remodeling through the synthesis and modification of ECM proteins, providing a favorable environment for cancer cell dissemination. Within the OC, the peptide endothelin-1 (ET-1), through two G protein-coupled receptors, ET A R and ET B R, supports tumor growth and progression by acting on both cancer and stromal cells. Many of these effects rely on the functional and molecular link with the protein b-arrestin1 (b-arr1). However, the precise role of ET-1 in regulating the expression of ECM proteins by primary human ovarian fibroblasts (HOFs) remains unclear. In this study, we aimed to elucidate the regulatory role of ET-1 in the expression of type I collagen (Col1) and fibronectin 1 (FN1). We report a significant increase in the expression of both Col1 and FN1 in cells stimulated with ET-1, both at mRNA and protein levels, reaching the amounts of proteins found in ovarian CAFs. The observed effects are associated with the activation of both receptors since they are impaired by treatment with either ET A R or ET B R antagonists in HOFs and CAFs. Furthermore, they are particularly affected by the dual ET A R/ET B R antagonist bosentan, in vitro and in vivo models. At the molecular level, ET-1 activates the Col1 promoter and enhances the expression of this gene through the nuclear function of β-arr1. The change in transcriptome of HOFs silenced for β-arr1 was analyzed to confirm the molecular response triggered by β-arr1, which resulted in the upregulation of ECM remodeling and collagen deposition. In summary, these findings demonstrate that the ET-1 axis may contribute to the remodeling of the ECM and probably to the early stages of OC progression by modulating the expression of Col1 and FN1. The targeting of ET-1 signaling with ET A R/ET B R antagonists may impede HOFs’ ability to produce key ECM proteins in this tumor.
2025-02-26 | GSE272256 | GEO
Project description:Alzheimer's disease (AD) is the most common cause of age-related dementia worldwide with limited effective treatments. Cerebral amyloid angiopathy (CAA) is one of the key pathological hallmarks of AD characterized by amyloid-β (Aβ) deposition in the cerebral vasculature and is associated with intracerebral hemorrhage, cerebrovascular dysfunction, and cognitive impairment. CAA is also considered to underlie the main adverse effect of anti-Aβ immunotherapies, the amyloid-related imaging abnormalities (ARIA). Substantial evidence from clinical and animal studies has shown that elevated levels of high-density lipoprotein (HDL), and its main protein component, apolipoprotein (APO) A-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide that has advanced into clinical trials for cardiovascular diseases. The present study aimed to investigate whether treatment with the HDL mimetic peptide 4F modulates CAA and associated cognitive deficits and neuropathologies in the well-established transgenic Tg-SwDI mouse model of CAA/AD. Age- and sex-matched Tg-SwDI mice received daily treatments of 4F or vehicle (PBS), respectively, by intraperitoneal injections for 12 weeks. The results showed that the 4F treatment reduced CAA as well as overall Aβ plaque deposition, and attenuated microgliosis associated with CAA. Unbiased brain transcriptomic analysis revealed a heightened inflammatory state in the brain of SwDI mice, and that 4F treatment reversed the overactivation of vascular cells, in particular vascular smooth muscle cells, relieving cerebrovascular inflammation in CAA/AD mice. Our study provides experimental evidence for the therapeutic potential of 4F to mitigate CAA and its associated pathogenic processes in AD, including ARIA.
2025-03-24 | GSE271286 | GEO
Project description:Purpose: To investigate the role of endothelial-mesenchymal transition (EndoMT) in pathological retinal angiogenesis and identify key molecular mediators in retina angiogenesis. Methods: RNA sequencing was performed on retinal tissue from oxygen-induced retinopathy (OIR) mouse model to analyze gene expression patterns. Gene Set Enrichment Analysis was used to examine the correlation between EMT and angiogenesis gene sets. Fibronectin (FN1) expression was evaluated in endothelial cells, and its function was assessed through siRNA mediated knockdown in both in vitro angiogenesis assays and the OIR model. Results: EndoMT occurred early in retinal angiogenesis development, with significant correlation between EMT and angiogenesis gene sets. FN1 was identified as the most significantly upregulated EMT-related gene in endothelial cells. siRNA-mediated inhibition of FN1 effectively prevented VEGF-induced angiogenesis in vitro and reduced pathological angiogenesis in the OIR model. Conclusions: EndoMT is a crucial early event in pathological retinal angiogenesis, with FN1 serving as a key mediator. Targeting FN1 may provide a novel therapeutic strategy that could synergize with anti-VEGF treatments to more effectively treat pathological angiogenesis in DR and ROP, particularly in cases of poor response to anti-VEGF therapy alone.
2025-03-19 | GSE289223 | GEO
Project description:Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence happens often with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin-integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Here, we identify c-Rel as an oncogenic driver in PDAC, promoting epithelial-to-mesenchymal transition (EMT) plasticity, extracellular matrix (ECM) remodeling, and resistance to isolation stress. Mechanistically, c-Rel directly regulates fibronectin (Fn1) and CD61 (itgb3) transcription, enhancing cellular plasticity and survival under anchorage-independent conditions. Fibronectin is not essential for EMT, but its absence significantly impairs metastatic colonization, highlighting a tumor-autonomous role for FN1 in isolation stress adaptation. These findings establish c-Rel as a key regulator of PDAC metastasis by controlling circulating tumor cell (CTC) niche and survival, suggesting that targeting the c-Rel–fibronectin–integrin axis could provide new therapeutic strategies to mitigate disease progression and recurrence.
2026-03-11 | GSE291961 | GEO
Project description:Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence happens often with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin-integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Here, we identify c-Rel as an oncogenic driver in PDAC, promoting epithelial-to-mesenchymal transition (EMT) plasticity, extracellular matrix (ECM) remodeling, and resistance to isolation stress. Mechanistically, c-Rel directly regulates fibronectin (Fn1) and CD61 (itgb3) transcription, enhancing cellular plasticity and survival under anchorage-independent conditions. Fibronectin is not essential for EMT, but its absence significantly impairs metastatic colonization, highlighting a tumor-autonomous role for FN1 in isolation stress adaptation. These findings establish c-Rel as a key regulator of PDAC metastasis by controlling circulating tumor cell (CTC) niche and survival, suggesting that targeting the c-Rel–fibronectin–integrin axis could provide new therapeutic strategies to mitigate disease progression and recurrence.
2026-03-11 | GSE291889 | GEO
Project description:The extracellular matrix (ECM), a key interface between the cerebrovasculature and other cells within the neuro-glial-vascular unit , provides structural stability and modulates cell behaviour and signalling. These functions are dependent on ECM protein composition. Since ECM defects may contribute to a broad range of disorders including cerebrovascular disease, it is crucially important to characterize ECM composition to better understand the mechanisms by which the ECM modulates brain health and disease. To date, molecular studies of the cerebrovascular ECM have been limited. We therefore generated ECM extracts from vascular enriched tissues of both mouse and human post-mortem brain. We used mass spectrometry with off-line high-pH reversed-phase fractionation to increase proteome depth and characterized the identified proteins. This identified a large number of proteins (>1000 mouse, >2000 human) in the ECM-enriched fractions, with > 66% of the identified proteins covered in both human and mouse samples. We now report 147 ECM proteins, including collagens (as major ECM components), laminins, fibronectin and nidogens, that can be considered as the core constituents of the human brain vascular matrisome. We also identified 12 novel proteins in the ECM-enriched fraction, that may have regulate or interact with the matrisome, including several key regulators of neurovascular interactions, such as BCAM, CDH5 and PARVB. Many of the identified brain vascular matrisome proteins are encoded by genes identified in stroke and cerebral small vessel disease genome-wide association studies, underscoring the importance of the vascular ECM in health and disease. This brain vascular matrisome represents a powerful resource for investigating the impact of aging and disease on the cerebrovasculature.
2021-03-11 | PXD020436 | Pride
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2026-02-09 | GSE304483 | GEO
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2024-02-29 | GSE256492 | GEO