Project description:To determine how gene expression is altered in aorta tissue in response to aortic aneurysm disease. Thoracic or abdominal aorta tissue was isolated from patients requiring surgery due to aortic aneurysm or other (control) reason.
Project description:Abdominal aortic aneurysm (AAA) is a permanent segmental dilatation of the abdominal aorta, contributing to a high mortality once rupture. We performed RNA-sequencing analysis of abdominal aorta tissues from 14 participants, including seven patients with AAA and seven control individuals.
Project description:In this study we used microarrays to examine relative genes expression within the aorta of ApoE-/- infused with angiotensin II in relation to aneurysm formation. Infusion of angiotensin II induces aortic dilatation particularly of the suprarenal aorta in ApoE-/- mice. Based on studies carried out in our and other laboratories the response to angiotensin II is variable, with some mice developing large aneurysms but other animals appearing resistant to aneurysm formation with aortic diameters similar to that of saline controls. We compared RNA expression from whole aortas of 17 week old male ApoE-/- mice exposed to angiotensin II (1.44 µg/kg/min) for 4 weeks where there was clear evidence of aortic aneurysm formation (n=5) with that of mice failing to develop aneurysms (n=7) and those exposed to saline infusion (n=6). AAA was defined as diameter of suprarenal aorta greated than 1.5mm measured on photographs of aortas at necroscopy. Keywords: Disease state analysis 18 samples analysed, AAA (n=5), no AAA (n=7), saline (n=6). AAA - abdominal aortic aneurysm
Project description:The ApoE -/- mice model of abdominal aortic aneurysm (AAA) involves introducing Angiotensin II subcutaneously to 14 week old male mice for 4 weeks by osmotic pump. A significant number of mice will develop aneurysm-like dilations in the suprarenal section of the abdominal aorta (SRA) that have a number of similarities to the human condition and make this a useful model of AAA. The mouse infrarenal aorta is very resistant to aneurysm formation while in humans AAA predominately occurs in the infrarenal section of the aorta (IRA). There have been a number of theories proposed to explain the site selctivity of aneurysm formation in AAA and this mice model. This study was designed to ascertain differences between SRA and IRA that may explain this site selectivity. Keywords: tissue type comparison
Project description:Aortic aneurysms is increasing as the human population ages. Pathological oxidative stress is implicated in development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line DAAO-TGTie2 that expresses yeast D-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generates the reactive oxygen species hydrogen peroxide (H2O2) in endothelial cells only when provided with D-amino acids. When DAAO-TGTie2 mice are chronically fed D-alanine, the animals become hypertensive and develop abdominal but not thoracic aortic aneurysms. Generation of H2O2 in the endothelium leads to oxidative stress throughout the vascular wall. Proteomic analyses indicate that the oxidant-modulated protein kinase JNK1 is dephosphorylated by the phophoprotein phosphatase DUSP3 in abdominal but not thoracic aorta, causing activation of KLF4-dependent transcriptional pathways that trigger phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocks aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds, and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.
Project description:The aim of this study was to explore the transciptome of the diverse vascular smooth muscle cells subsets from abdominal aortic aneurysm tissues in Gsdme deletion mice.The model was established by exposing the infrarenal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration for 4 weeks.we compared the characteristics of SMC subpopulation beteew the WT and KO groupsto reveal the effect of GSDME in the progression of Abdomanl Aortic Aneurysm.
Project description:Pathologies of large vessels, such as atherosclerosis and aneurysms tend to develop at specific sites in the vascular tree. The consistency with which these events emerge suggests that a combination of unique local stressors, particularly physical forces and disturbances in gene expression profiles underlies disease etiology. We sought to investigate whether transcriptional diversity in specific segments of the aorta could be used to identify emergence of site-restricted vascular disease. Transcriptional profiling was performed using single cell RNA-seq in the carotids, aortic arch, thoracic and abdominal aorta across both sexes. Analyses of the data identified sex-invariant region-specific differences that were further validated by immunocytochemistry. Analysis of vascular smooth muscle cell transcriptomics from distinct regions of the aorta and carotids showed a high degree of similarity, but also uncovered skewed expression of a small percentage of transcripts (7.2%) towards particular vascular segments (carotid, aortic arch, thoracic and abdominal aorta). In silico cross-reference of genes known to be associated with vascular disease with the unique transcriptional signatures validated our proposed hypothesis. Specifically, we found correlations between localized-diseased causing GWAS candidate genes and region-enriched signatures. Pair-wise comparison between anatomic regions across sexes identified regional sex-specific gene signatures highlighting prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. Of these regional sex-enriched candidates’, Mcam/CD146, showed ventral thoraco-abdominal distribution, enriched expression in females and it was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm. Furthermore, induction of aneurysms in mice lacking Mcam/CD146 resulted in larger lesions and accelerated death due to dissection.
Project description:Vascular smooth muscle cell (VSMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts a myriad of context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here we report the effect of SMC-restricted CCN2 deficiency of hypercholesterolemic mice on gene expression in infrarenal aorta with or without angiotensin II (Ang II)-infusion.
Project description:The long non-coding RNA NUDT6 was found to be deregulated in abdominal aortic aneurysm (AAA) with higher expression in diseased human tissue specimens versus control aortic tissue. Apart from the already well-studied DNA: RNA interaction as a natural antisense transcript to Fibroblast Growth Factor 2 (FGF2), we were interested in identifying protein interaction partners to unravel further involvement in the pathogenesis and progression of abdominal aortic aneurysm. Therefore, we performed a RNA pulldown experiment using biotinylated NUDT6 and control RNA in human aortic smooth muscle cell lysate to identify further interaction partners.