Cerebrovascular p16INK4A expression induces cerebral small vessel disease-related phenotypes
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PROVIDER: PRJNA1302351 | ENA |
REPOSITORIES: ENA
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Project description:Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.
2025-08-20 | GSE304696 | GEO
Project description:Background The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved. Methods Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamideinduced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels. Results AGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endotheliumdependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP. Conclusions AGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulatingthe expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.
2024-12-24 | GSE253928 | GEO
Project description:Cerebrovascular injuries can cause severe edema and inflammation that adversely affect human health. Here, we observed recanalization after successful endovascular thrombectomy for acute large vessel occlusion was associated with cerebral edema and poor clinical outcomes in patients who experienced hemorrhagic transformation. To understand this process, we developed a cerebrovascular injury model using transcranial ultrasound that enabled spatiotemporal evaluation of resident and peripheral myeloid cells. We discovered that injurious and reparative responses diverged based on time and cellular origin. Resident microglia initially stabilized damaged vessels in a purinergic receptor-dependent manner, which was followed by influx of myelomonocytic cells that caused severe edema. Prolonged blockade of myeloid cell recruitment with anti-adhesion molecule therapy prevented severe edema but also promoted neuronal destruction and fibrosis by interfering with vascular repair later orchestrated by pro-inflammatory monocytes and pro-angiogenic repair-associated microglia (RAM). These data demonstrate how temporally distinct myeloid cell responses can contain, exacerbate, and ultimately repair a cerebrovascular injury.
2021-02-10 | GSE161424 | GEO
Project description:This study aims at a comprehensive understanding of the genomic program activated during early-phase of collateral vessel growth in a rat model for cerebral adaptive arteriogenesis (3-VO). While arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischemia, genomic profiles essential for therapeutic target identification were analysed solely for collateral arteries of the heart and periphery. Despite challenging anatomical conditions of the brain the 3-VO model allows identification of differentially expressed genes during adaptive cerebral arteriogenesis by selective removal of the posterior cerebral artery (PCA). Keywords: early response time course, selective collateral growth, brain
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Project description:HTRA1 Mutation and Expression Regulation in Cerebral Small Vessel Disease
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Project description:To further explore the mechanism of cerebrovascular pruning by PD1 in microglia, we analyzed RNA isolated from Pd1fl/fl and Pd1cKO-Cx3 cerebral cortical microglia at P11 using RNA-seq to identify genome-wide changes.
2024-09-10 | GSE276402 | GEO
Project description:This study aims at a comprehensive understanding of the genomic program activated during early-phase of collateral vessel growth in a rat model for cerebral adaptive arteriogenesis (3-VO). While arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischemia, genomic profiles essential for therapeutic target identification were analysed solely for collateral arteries of the heart and periphery. Despite challenging anatomical conditions of the brain the 3-VO model allows identification of differentially expressed genes during adaptive cerebral arteriogenesis by selective removal of the posterior cerebral artery (PCA). Experiment Overall Design: Using an established rat model of nonischemic cerebral hypoperfusion (3-VO) (Busch, Buschmann; 2003), RNA was extracted from isolated ipsilateral PCA. Pooled RNAs from groups of intact (0h), sham and 3-VO animals 24h and 3 days after surgery, were hybridised repeatedly for an extensive genome screen of 15866 genes applying standardized Affymetrix technology. For each Array total RNA from 8 animals was processed, pooled and hybridized to a Rat230A GeneChip per group. These groups were classified as follows: intact control (N=3), 24h3VO (N=3); 24h sham (N=3), 3days3VO (N=3); and 3days sham(N=3). Hybridization, washing, antibody amplification, staining, and scanning of probe arrays were performed according to the Affymetrix Technical Manual. Probe arrays were scanned using the GeneChip System (Hewlett-Packard, Santa Cruz, CA)(Affymetrix) and raw data were processed using GCOS and normalized to a global intensity of 500.
2008-10-25 | E-GEOD-6189 | biostudies-arrayexpress
Project description:Cerebral small vessel disease (CSVD) refers to a series of clinical, radiological, and pathological syndromes caused by various etiologies affecting small arteries, arterioles, venules, capillaries, and small veins in the brain. It can lead to cognitive impairment, stroke, gait abnormalities, and other neurological symptoms and signs. Globally, approximately 25% to 30% of strokes are caused by CSVD. The underlying mechanisms of CSVD are multifaceted, involving endothelial dysfunction, blood-brain barrier (BBB) inflammation, neuronal apoptosis, chronic cerebral hypoperfusion, and their complex interactions. Current treatments often fail to achieve satisfactory outcomes. Therefore, understanding the pathogenic mechanisms of CSVD is crucial for developing effective therapeutic strategies to mitigate its detrimental effects. The high-temperature requirement protease A-1 (HTRA1) mutations can cause hereditary CSVD. CSVD associated with HTRA1 mutations is referred to as HTRA1-associated CSVD. Homozygous HTRA1 mutations cause Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), a rare hereditary CSVD that is inherited in an autosomal recessive manner. Heterozygous HTRA1 mutations can lead to Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy type 2 (CADASIL 2), also known as heterozygous HTRA1 mutation carriers. This condition is characterized by clinical manifestations such as stroke, cognitive impairment, gait abnormalities, alopecia, and spondylosis. To date, 35 pathogenic mutations in the HTRA1 gene have been reported, primarily exhibiting autosomal dominant inheritance. Current research mainly focuses on case reports and the potential pathogenic mechanisms associated with different mutation sites. HTRA1 mutations can lead to downregulation of HTRA1 mRNA and protein expression, thereby reducing HTRA1 protease activity. However, the specific morphological and functional changes associated with CSVD, especially those in endothelial cells, remain unclear. This study aims to explore the mutation spectrum and clinical phenotypes of heterozygous HTRA1 mutation carriers. By comparing whole-blood RNA sequencing (RNA-seq) analysis between heterozygous HTRA1 mutation carriers and healthy controls, we identify differentially expressed genes. Based on the RNA-seq results, we further investigate the effects of abnormal HtrA1 expression on the biological functions of mouse brain microvascular endothelial cells and mouse cognitive behavior. This study elucidates the role of HTRA1 in CSVD, providing insights into the pathogenesis and new therapeutic targets for patients with heterozygous HTRA1 mutations.
2026-03-11 | GSE324041 | GEO
Project description:Introduction: Cerebral small vessel disease (SVD), manifesting as white matter hyperintensities (WMH), lacunar infarctions, and cerebral microbleeds on MRI, has been linked to epigenetic alterations. Methods: Genome-wide promoter methylation was profiled using the Infinium MethylationEPIC v2.0 array in peripheral inflammatory cells from 16 patients without SVD and 16 patients with all three imaging features. Results: EPIC profiling identified 17 promoter regions with significant differences between groups, and CDH7 hypomethylation emerged as an independent predictor of SVD imaging features. Conclusion: CDH7 hypomethylation was identified and validated as an epigenetic marker predictive of MRI-defined SVD imaging features.
2026-04-01 | GSE318387 | GEO
Project description:Pro-inflammatory monocyte phenotype during acute progression of cerebral small vessel disease
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