| 1. |
- Björck, Hanna M., et al.
(författare)
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Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Shear forces play a key role in the maintenance of vessel wall integrity. Current understanding regarding shear-dependent gene expression is mainly based on in vitro or in vivo observations with experimentally deranged shear, hence reflecting acute molecular events in relation to flow. Our objective was to determine wall shear stress (WSS) in the rat aorta and study flow-dependent vessel wall biology under physiological conditions.Methods and Results: Animal-specific aortic WSS magnitude and vector direction were estimated using computational fluid dynamic simulation based on aortic geometry and flow information acquired by MRI. Two distinct flow pattern regions were identified in the normal rat aorta; the distal part of the inner curvature being exposed to low WSS and a non-uniform vector direction, and a region along the outer curvature being subjected to markedly higher levels of WSS and a uniform vector direction. Microarray analysis revealed a strong differential expression between the flow regions, particularly associated with transcriptional regulation. In particular, several genes related to Ca2+-signalling, inflammation, proliferation and oxidative stress were among the most highly differentially expressed.Conclusions: Microarray analysis validated the CFD-defined WSS regions in the rat aorta, and several novel flow-dependent genes were identified. The importance of these genes in relation to atherosusceptibility needs further investigation.
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| 2. |
- Fegraeus, Kim, et al.
(författare)
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An endothelial regulatory module links blood pressure regulation with elite athletic performance
- 2024
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 20:6
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Tidskriftsartikel (refereegranskat)abstract
- The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.
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| 3. |
- Forsell, Caroline, et al.
(författare)
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Biomechanical Properties of the Thoracic Aneurysmal Wall : Differences Between Bicuspid Aortic Valve and Tricuspid Aortic Valve Patients
- 2014
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 98:1, s. 65-71
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Tidskriftsartikel (refereegranskat)abstract
- Background. The prevalence for thoracic aortic aneurysms (TAAs) is significantly increased in patients with a bicuspid aortic valve (BAV) compared with patients who have a normal tricuspid aortic valve (TAV). TAA rupture is a life-threatening event, and biomechanics-based simulations of the aorta may help to disentangle the molecular mechanism behind its development and progression. The present study used polarized microscopy and macroscopic in vitro tensile testing to explore collagen organization and mechanical properties of TAA wall specimens from BAV and TAV patients. Methods. Circumferential sections of aneurysmal aortic tissue from BAV and TAV patients were obtained during elective operations. The distribution of collagen orientation was captured by a Bingham distribution, and finite element models were used to estimate constitutive model parameters from experimental load-displacement curves. Results. Collagen orientation was almost identical in BAV and TAV patients, with a highest probability of alignment along the circumferential direction. The strength was almost two times higher in BAV samples (0.834 MPa) than in TAV samples (0.443 MPa; p < 0.001). The collagen-related stiffness (C-f) was significantly increased in BAV compared with TAV patients (C-f = 7.45 MPa vs 3.40 MPa; p = 0.003), whereas the elastin-related stiffness was similar in both groups. A trend toward a decreased wall thickness was seen in BAV patients (p = 0.058). Conclusions. The aneurysmal aortas of BAV patients show a higher macroscopic strength, mainly due to an increased collagen-related stiffness, compared with TAV patients. The increased wall stiffness in BAV patients may contribute to the higher prevalence for TAAs in this group.
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| 4. |
- Freiholtz, David, et al.
(författare)
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SPP1/osteopontin : a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?
- 2023
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Ingår i: Journal of Molecular Medicine. - : Springer Nature. - 0946-2716 .- 1432-1440. ; 101:10, s. 1323-1333
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Degenerative ascending aortic aneurysm (AscAA) is a silent and potentially fatal disease characterized by excessive vascular inflammation and fibrosis. We aimed to characterize the cellular and molecular signature for the fibrotic type of endothelial mesenchymal transition (EndMT) that has previously been described in degenerative AscAA. Patients undergoing elective open-heart surgery for AscAA and/or aortic valve repair were recruited. Gene expression in the intima-media of the ascending aorta was measured in 22 patients with non-dilated and 24 with dilated aortas, and candidate genes were identified. Protein expression was assessed using immunohistochemistry. Interacting distal gene enhancer regions were identified using targeted chromosome conformation capture (HiCap) in untreated and LPS-treated THP1 cells, and the associated transcription factors were analyzed. Differential expression analysis identified SPP1 (osteopontin) as a key gene in the signature of fibrotic EndMT in patients with degenerative AscAA. The aortic intima-media expression of SPP1 correlated with the expression of inflammatory markers, the level of macrophage infiltration, and the aortic diameter. HiCap analysis, followed by transcription factor binding analysis, identified ETS1 as a potential regulator of SPP1 expression under inflammatory conditions. In conclusion, the present findings suggest that SPP1 may be involved in the development of the degenerative type of AscAA. Key messages: In the original manuscript titled “SPP1/osteopontin, a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?” by David Freiholtz, Otto Bergman, Saliendra Pradhananga, Karin Lång, Flore-Anne Poujade, Carl Granath, Christian Olsson, Anders Franco-Cereceda, Pelin Sahlén, Per Eriksson, and Hanna M Björck, we present novel findings on regulatory factors on osteopontin (SPP1) expression in immune cells involved in degenerative ascending aortic aneurysms (AscAA). The central findings convey: SPP1 is a potential driver of the fibrotic endothelial-to-mesenchymal transition in AscAA.SPP1/osteopontin expression in AscAA is predominately by immune cells.ETS1 is a regulatory transcription factor of SPP1 expression in AscAA immune cells.
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| 5. |
- Maleki, Shohreh, et al.
(författare)
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Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve
- 2013
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Ingår i: Journal of Molecular Medicine. - : Springer-Verlag New York. - 0946-2716 .- 1432-1440. ; 91:1, s. 129-139
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Individuals with bicuspid aortic valve (BAV) are at significantly higher risk of developing serious aortic complications including aortic aneurysm and dissection than individuals with a tricuspid aortic valve (TAV). Studies have indicated an altered aortic blood flow in patients with BAV, however the extent to which altered flow may influence the pathological state of BAV aorta is still unclear.Objective: To dissect flow-mediated gene expression potentially leading to increased aneurysm susceptibility in patients with BAV.Methods and Results: A large collection of publically available microarray data sets were screened for consistent co-expression with KLF2, KLF4, TIE1, THBD, and PKD2, five previously well-characterized flow-regulated genes. This identified 122 genes with coexpression probability of >0.5. Of these, 44 genes satisfied two additional filtering criteria in ascending aorta (127 arrays). The criteria were significant correlation with one or more of the 5 query genes (R>0.40) and differential expression between patients with BAV and TAV. No gene fulfilled the criteria in mammary artery (88 arrays). A large proportion of the identified genes were angiogenesis related genes. Further, 55% of the genes differentially expressed between BAV and TAV showed differential expression in disturbed vs. uniform flow pattern regions in rat aorta. Protein expression of ZFP36, PKD2 and GPR116 were analyzed by immunohistochemistry and their association with BAV were further discussed.Conclusions: With a new strategy to dissect flow-mediated gene expression, we identified novel genes associated with valve morphology. The complex pattern of blood flow, as a consequence of BAV
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