MERSCOPE profiling of non-aneurysmal and aneurysmal human ascending aorta
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE241870 | GEO | 2023/10/14
REPOSITORIES: GEO
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Project description:To identify miRNAs which could be involved in TAA (Thoracic Aortic Aneurysm) pathogenesis, we first performed miRNAs microarrays using the aortic media of healthy controls and TAA patients. 473 miRNAs were detected in at least half samples. Among them, 232 miRNAs were differentially expressed with adjusted p value < 0.05 and log2 transformed fold change > 0.5 or < -0.5.
2019-09-18 | GSE110527 | GEO
Project description:In current models of ascending aortic disease, mural cells undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore the intersection of this biology with quantitative trait GWAS loci we analyzed the genetic features of thoracic aortic aneurysm tissue. Single nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. In total, we sequenced 71,689 nuclei from human thoracic aortas without aneurysm, and with sporadic aneurysm. We identified 14 clusters, aligning with 11 cell types, predominantly VSMCs, consistent with existing histologic data, but contrary to the majority of human aortic single cell studies to-date. With unbiased methodology, we found 7 VSMC and 6 fibroblast subclusters. Differentially expressed genes (DEGs) analysis revealed a VSMC group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. DEGs were used to prioritize genes at aortic diameter and distensibility GWAS loci highlighting the genes JUN, LTBP4, and IL34 in fibroblasts, ENTPD1, PDLIM5, ACTN4, and GLRX in VSMCs, as well as LRP1 in macrophage populations. In conclusion, using nuclear RNA sequencing we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.
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Project description:High throughput miRNA microarray screening approach, we compared the miRNA expression pattern in ruptured aneurysm tissues obtained during surgery from patients with aneurysmal subarachnoid hemorrhage (aSAH) with control tissues. Aim was to determine miRNA signature in aneurysmal tissues.
2020-11-21 | GSE161870 | GEO
Project description:We analyzed differentially expressed genes in smooth muscle cells derived from the thoracic aorta of Marfan Syndrome (MFS) patients and control subjects to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify a potential drug treatment to mitigate TAA progression. We analyzed differentially expressed genes in whole aorta of P16 MFS mice vs WT mice to identify cell biological mechanisms contributing to thoracic aoritc aneurysm (TAA) development and rupture. These mechanisms were used to identify baclofen as a potential drug treatment to mitigate TAA progression. The effect of baclofen on gene expression in WT and MFS was documented in P60 mice that received treatment since P16.
2019-11-18 | GSE128101 | GEO
Project description:Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. In this study, protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. To verify it, we constructed aorta-on-a-chip to replicate the rhythmic tensile on human aorta, on which human aortic smooth muscle cells (HAoSMCs) endured a microenvironment of biomimetic strain unattainable in animal models. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) rescued the mitochondrial dysfunction in HAoSMCs from BAV-TAA patients. These findings suggest that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.
2021-09-11 | PXD026303 | Pride
Project description:Aneurysm and dissection of the aortic root is a common cause of morbidity and mortality in Loeys-Dietz Syndrome (LDS) and Marfan Syndrome (MFS), where perturbations in TGF β signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling for mechanistic studies and pre-clinical drug discovery, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish larvae, homozygous for null mutations in latent TGF β binding proteins (ltbps) 1 and 3, develop rapid and severe aneurysmal dilatation of the aortic root equivalent, the outflow tract (OFT), after grossly unperturbed cardiac morphogenesis. The ventricle also becomes significantly dilated and upregulates stress-responsive genes, which likely reflects compensatory pathologic remodeling since ltbp1 and ltbp3 co-expression is restricted to the OFT. Similar to aneurysm tissue from LDS and MFS patients, the distended OFTs display evidence for hyperactivated TGF β signaling. Moreover, RNA-sequencing revealed significant overlap between the molecular signatures of diseased tissue from double knockout zebrafish and MFS mice. Lastly, chemical inhibition of the TGF β Type I receptor in wild-type embryos evoked similar OFT and ventricular dilation phenotypes, demonstrating that TGF β signaling is protective against these pathologies. The disease relevance of the mutant phenotype is further supported by recent family studies implicating genetic lesions in Ltbp3, and likely Ltbp1, as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that the unique advantages of zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small molecule suppressor screens.
2022-04-19 | GSE152389 | GEO
Project description:OBJECTIVE: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined the transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to angiotensin II (AngII) infusion and determined its importance in protecting against aortic aneurysm and dissection. APPROACH AND RESULTS: In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by the upregulation of genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and AKT and TGF-β signaling. Further single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analysis showed increased chromatin accessibility at the regulatory regions of adaptive genes and revealed the mechanical sensor YAP/TEADs as a top candidate transcription complex driving the increased abundance of these gene transcripts (e.g., Lox, Col5a2 and Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to the regulatory regions of the adaptive genes (e.g., Lox) and increased the abundance of their transcripts. Finally, SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased incidence of aortic aneurysm and dissection and a trend of increased rupture. CONCLUSIONS: Aortic stress triggers the systemic epigenetic induction of adaptive response (e.g., wound healing, proliferation, and matrix organization) in thoracic aortic SMCs, that depends on functional biomechanical signal transduction (e.g., YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing aortic disease development in mice.
2023-02-01 | GSE214082 | GEO
Project description:Wall shear stress (WSS) is proposed to influence intracranial aneurysm growth and rupture. Physiological WSS in cerebral arteries is estimated around 20-30 dynes/cm2. The WSS typically observed in human IAs is close to 2 dynes/cm2 for wide-neck aneurysms with a slow recirculating flow and >70 dynes/cm2 in aneurysms with impinging “jet flow”. In this study, we investigated the effects of aneurysmal low and supra-high WSS on endothelial cells.
2021-11-04 | GSE173928 | GEO
Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).
2018-01-30 | GSE109797 | GEO
Project description:Aortic aneurysms are dilations of the aorta that can rupture when left untreated. We used aneurysmal Fibulin-4R/R to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old Fibulin-4R/R aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of Fibulin-4R/R VSMCs by revealing increased SA-β-gal, p21 and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of Fibulin-4R/R|p21-Luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that Fibulin-4R/R aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK/STAT and TGF-β pathway inhibition as well as senolytic treatment on Fibulin-4R/R VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.
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