Project description:The purpose of this study was to determine whether lysyl oxidase inhibition using β-aminopropionitrile (BAPN) induced region-specific aortopathies in mice. The effects of BAPN were first characterized with regard to dose, strain, age, and sex. Subsequently, BAPN was administered to young male C57BL/6J mice. BAPN-induced aortic rupture predominantly occured or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while relatively sporadic in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissection with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the media and adventitia. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, while RNA sequencing demonstrated that BAPN altered transcriptomes related to extracellular matrix and cell division differentially between the two regions. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice.
Project description:Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, revealing 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests, and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (HR = 1.43 per SD; CI 1.32-1.54; P = 3.3·10-20). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.
Project description:Comparisons of canine arterial gene expression between control and untreated MPS animals were conducted with a canine-specific microarray covering 43,803 probes (Agilent G2519F 4x44k, Santa Clara, CA), for a total of four comparison groups: MPS ascending aorta vs. control ascending aorta, MPS descending aorta vs. control descending aorta, MPS carotid artery vs. control carotid artery, and finally pooled MPS artery (ascending aorta, descending aorta, carotid artery) vs. pooled control artery. Each comparison used four pairs of MPS vs corresponding age- and gender- matched animals to produce four biologic replicates.
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.
Project description:Fibulin-4 plays an essential role in elastic fiber formation, though it's exact function is unclear. Mice lacking the fibulin-4 gene develop cutis laxa with thoracic aortic aneurysms and have narrowed descending aortic diamaters, dying shortly after birth. Another model that disrupt elastic fiber formation, elastin gene knockeds, are also perinatally lethal and have narrowed descending aortas but do not develop thoracic aneurysms. We hypothesized that there may be altered gene expression to explain the altered anatomy based on aortic tissue location we observed, which may provide therapeutic target(s) Ascending and descending aortas of p0 mouse pups were dissected, pooled in groups of eight, and homogenized to isolate RNA and we used microarrays on the pooled samples to identify genes that had expression significantly changed.
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:Transcriptome analysis of human primary smooth muscle cells from different arterial beds (abdominal and thoracic aorta, carotid and femoral and infrapopliteal arteries).
Project description:We adopted a transcriptome-wide microarray analysis approach to determine the extent to which vascular gene expression is altered as a result of juvenile obesity and identify obesity-responsive mRNAs. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n=5) and lean (n=6) juvenile Ossabaw pigs (age=22 weeks). Obesity was experimentally induced by feeding the animals a high-fat/high fructose corn syrup/high-cholesterol diet for 16 weeks. We found that expression of 189 vascular cell genes in the LAD and expression of 165 genes in the thoracic aorta were altered with juvenile obesity (FDRM-bM-^IM-$10%) with an overlap of only 28 genes between both arteries. Notably, a number of genes found to be markedly up-regulated in the LAD of obese pigs are implicated in atherosclerosis, including ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, and P2RY12. Furthermore, pathway analysis revealed the induction of pro-inflammatory and pro-oxidant pathways with obesity primarily in the LAD. Gene expression in the LAD perivascular fat was minimally altered with juvenile obesity. Together, we provide new evidence that obesity produces artery-specific changes in pre-translational regulation with a clear up-regulation of pro-atherogenic genes in the LAD. Our data may offer potential viable drug targets and mechanistic insights regarding the molecular precursors involved in the origins of over-nutrition and obesity-associated vascular disease. In particular, our results suggest that the oxLDL-LOX-1-NFM-NM-:B signaling axis may be involved in the early initiation of a juvenile obesity-induced pro-atherogenic coronary artery phenotype. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n=5) and lean (n=6) juvenile Ossabaw pigs (age= 22 weeks). All three tissue types were taken from each animal, and each was applied to one and only one array array except a single Thoracic aorta (Animal ID 63 because there were not enough arrays), so there were 32 total arrays (11 unique pigs).
Project description:Uremic media calcification is not only driven by systemic factors such as hyperphosphatemia, but also crticially dependent on vascular smooth muscle cells per se. We hypothesized that the different developmental origins of vscular smooth muscle cells might lead to a heterogeneous susceptibility to develop media calcification. Upon high-phosphate diet, the transcriptional profile revealed an induction of an inflammatory vascular smooth muscle phenotype only in the abdominal, but not in the thoracic aorta. Thus, smooth muscle cells from different lineages responded differently to morphogenetic cues in vivo. We analyzed 3-4 replicates of the thoracic and abdominal aorta, which were previously exposed to either high-phosphate diet (HPD) or standard chow diet (SCD), respectively.