Murine Marfan Syndrome Sildenafil Treatment
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ABSTRACT:
PROVIDER: PRJNA527824 | ENA |
REPOSITORIES: ENA
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Project description:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.
2019-03-19 | GSE128481 | GEO
Project description:We report dynamic temporal and spatial smooth muscle cell phenotype modulation using aortic single cell RNA sequencing in a murine model of Marfan syndrome (Fbn1C1041G/+) and littermate controls. Aortic root/ascending aortic tissue samples from both genotypes were studied at 4 and 24 weeks of age. The non-aneurysmal descending thoracic aorta was also studied at 24 weeks. Finally human aortic tissue from a Marfan syndrome patient undergoing aneurysm repair surgery was studied.
2020-06-30 | GSE153534 | 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:The goal of this study is to define the main tissue and mechanism implicated in the long bone overgrowth phenotype in mice with Marfan syndrome
2022-10-11 | GSE189091 | 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:Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts
2007-09-14 | GSE8759 | GEO
Project description:Aortic smooth muscle cell (SMC) phenotype modulation is a central feature of cell-mediated pathology in Marfan syndrome aortic aneurysm and Klf4 is proposed to contribute to this process. We generated mice with smooth muscle cell-specific Klf4 deletion using an Myh11-creERT2 transgene, induced deletion at 8 weeks and performed single cell RNA sequencing at 24 weeks on whole aortic root tissues.
2022-08-23 | GSE206227 | GEO
Project description:Thoracic aortic aneurysms have a higher prevalence in male patients compared to female patients. Marfan syndrome causes a hereditary form of TAA with dilation of the aortic root. Male patients with Marfan syndrome are more likely than women to have aortic dilation and dissection and mouse models of Marfan syndrome demonstrate larger aortic roots in males compared to females even after adjustment for body size. Similar sex disparities are present in patients and models of abdominal aortic aneurysms where estrogen has been demonstrated to attenuate aneurysm formation perhaps through anti-inflammatory mechanisms. In this study we demonstrate the effects of estrogen on aortic dilation and rupture in a Marfan mouse model and we investigate if these effects operate through suppression of complement components of the immune system.
2024-02-14 | PXD037853 | Pride