Single cell RNA sequencing of SMC specific Yap1 knockout mouse aorta
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213735 | GEO | 2023/02/01
REPOSITORIES: GEO
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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:Aortic tissues of developing and established aneurysms produced by angiotensin II (AngII) infusion were examined in Apoe-/- and Ldlr-/- mice. Aortas were also acquired from wildtype C57BL/6J mice following intraluminal elastase incubation. Aortas were dissected free and separated into eight anatomical segments for proteomics in comparison to their appropriate controls. In addition, proteomics was performed on human infrarenal aortic aneurysm tissues as well as aortic tissue collected from age-matched controls.
2022-08-02 | PXD032293 | Pride
Project description:Objective-Aortic pathologies exhibit sexual dimorphism, with aneurysms in the ascending, thoracic and abdominal aorta (AAA) exhibiting higher prevalence in males. Despite lower incidence of aortic vascular disease in women, aneurysms progress rapidly. Mechanisms for these sex differences are unclear. We defined the role of sex chromosome complement and testosterone in regional development and progression of angiotensin II (AngII)-induced vascular pathologies. Approach and Results-We used transgenic male mice expressing Sry on an autosome to create low density lipoprotein receptor (Ldlr) deficient male mice with an XY or XX sex chromosome complement. Subjects were then sham operated or orcheictomized. Transcriptional profiling on abdominal aortas from XY or XX males demonstrated1746 genes influenced by sex chromosomes, sex hormones, or an interaction. A second cohort of animals was then infused with AngII for 28 days. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, while XX males developed discrete AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males, but not XX males exhibited adventitial thickening. We infused male XY and XX mice with saline or AngII and quantified mRNA abundance of key genes in thoracic versus abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in AAA aortic wall thickening in XY males with diffuse aortic pathology, while XX males had dilated focal AAAs. Conclusions-An XY sex chromosome complement mediates diffuse aortic pathology, while an XX sex chromosome complement contributes to discrete AngII-induced AAAs.
2018-07-22 | GSE102143 | GEO
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
2010-06-24 | E-GEOD-12591 | biostudies-arrayexpress
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
2010-05-12 | GSE7006 | GEO
Project description:Objective - Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic extracellular matrix (ECM). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. Approach and Results - A model of aortic dilatation by angiotensin II (AngII) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure whilst displaying increased dilatation of the ascending aorta. Interestingly, a comparison of the aortic ECM from AngII-treated wildtype and Adamts5Δcat mice revealed versican as the most up-regulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of low-density lipoprotein-related protein 1 (LRP1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice, but was not sufficient to maintain versican processing and prevent aortic dilatation. Conclusions - Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.
2018-05-08 | PXD009410 | Pride
Project description:Objective: Turner Syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of angiotensin II (AngII)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of AngII-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XXF or XOF) on an C57BL/6J (ascending aortopathies) or Ldlr-/- background (descending and abdominal aortopathies) compared to XY males (XYM). To induce aortopathies, mice were infused with AngII. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than AngII-infused XXF or XYM. AngII-infused XOF (Ldlr-/-) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended AngII infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.02 ± 0.17; XOF, 1.96 ± 0.32 mm; P=0.027) persisted in ovariectomized AngII-infused XOF mice. Data from RNA seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a), exhibited lower mRNA abundance in aortas of XOF than XXF (P=0.033 and 0.024 respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF (P=0.038). Conclusion: The absence of a second X chromosome promotes diffuse AngII-induced aortopathies in females.
2021-06-27 | GSE154036 | GEO
Project description:The present study was undertaken to test the hypothesis that EPO may promote the formation of abdominal aortic aneurysm (AAA) via angiogenesis and inflammatory response. We injected EPO in different doses to Apoe-/- and WT mice, used EPO mAb in Apoe-/- mice with AngII stimulation, injected a selective activator of the heterodimer receptors of EPO into Apoe-/- and WT mice, and created CRISPR-mediated EPOR knockout (Epor+/-Apoe-/-) mice. In addition, we measured serum EPO concentration in healthy controls and patients with AAA, and performed a series of in vitro and ex vivo experiments in ECs, SMCs, and macrophages. Our results showed that EPO dose-dependently promoted the formation of AAA, with a high occurrence rate in both Apoe-/- and WT mice, and there was a close relationship between serum concentration of EPO and the incidence of AAA in Apoe-/- and WT mice receiving AngII or EPO treatment. The major mechanism involved angiogenesis, inflammatory response, SMCs apoptosis and collagen degradation via EPO-EPOR-JAK2/STAT5 signaling pathway in vascular cells. Administration of EPO neutralizing antibody suppressed AngII-induced AAA formation, and the incidence of AAA was dramatically reduced in Epor+/-Apoe-/- versus Apoe-/- mice after AngII infusion. In addition, serum EPO concentration was substantially higher in patients with AAA than in healthy subjects and correlated with the size of AAA in patients. In conclusion, EPO promotes the formation of AAA in both Apoe-/- and WT mice likely via enhanced angiogenesis, inflammation, SMCs apoptosis and collagen degradation, and EPO/EPOR signaling is essential for AngII-induced and possibly human AAA.
2021-05-18 | GSE174556 | GEO
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
2009-08-26 | GSE12591 | GEO
Project description:This study aims to identify and characterize miRNA expression in aneurysmal smooth muscle cells (SMCs) and M1 and M2 macrophages isolated by laser microdissection from human AAA biopsy samples. The aim of this study was to profile (with microarray technology) miRNAs in M1 and M2 macrophages and Smooth muscle cells (SMCs), isolated by laser capture microdissection (LCM). SMCs isolated from control non-aneurysmal aortas were the control group according to which data were normalized. Areas enriched in M1 macrophages, M2 macrophages and smooth muscle cells were microdissected (9.8 [4.7-16.2] mm2) from two different biopsy samples of human abdominal aortic aneurysm. An area enriched in smooth muscle cells was microdissected from two biopsy samples of non aneurysmal abdominal aortas. Each microdissected samples were analyzed independently on microarray. M1 and M2 macrophages and smooth muscle cells expressed in human abdominal aneurysmal aortas were each analyzed in duplicate (each isolated from different human donors of abdominal aortic aneurysm). Analysis of replicated samples of cells were performed on a second microarray. Data were normalized with smooth muscle cells isolated from human abdominal non aneurysmal aortas.
2014-10-09 | E-GEOD-62179 | biostudies-arrayexpress