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Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor
Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Fysiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanisk värmeteori och strömningslära. Linköpings universitet, Tekniska högskolan.
Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Vise andre og tillknytning
2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2012. Vol. 7, nr 12
Emneord [en]
Aorta, wall shear stress, magnetic resonance imaging, computational fluid dynamics, gene expression
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-73954DOI: 10.1371/journal.pone.0052227ISI: 000312794500119OAI: oai:DiVA.org:liu-73954DiVA, id: diva2:479263
Tilgjengelig fra: 2012-01-17 Laget: 2012-01-17 Sist oppdatert: 2018-01-12
Inngår i avhandling
1. Vessel wall integrity: influence of genetics and flow
Åpne denne publikasjonen i ny fane eller vindu >>Vessel wall integrity: influence of genetics and flow
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.

The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.

Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.

Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.

Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2012. s. 84
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1270
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-73958 (URN)9789173930338 (ISBN)
Disputas
2012-01-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2012-01-17 Laget: 2012-01-17 Sist oppdatert: 2017-12-12bibliografisk kontrollert

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