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Vessel wall integrity: influence of genetics and flow
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1270
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-73958ISBN: 9789173930338 (print)OAI: oai:DiVA.org:liu-73958DiVA: diva2:479307
Public defence
2012-01-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-12-12Bibliographically approved
List of papers
1. Association of genetic variation on chromosome 9p21.3 and arterial stiffness
Open this publication in new window or tab >>Association of genetic variation on chromosome 9p21.3 and arterial stiffness
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2009 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 265, no 3, 373-381 p.Article in journal (Refereed) Published
Abstract [en]

Genome wide association studies have consistently reported associations between a region on chromosome 9p21.3 and a broad range of vascular diseases, such as coronary artery disease (CAD), aortic and intracranial aneurysms and type-2 diabetes (T2D). However, clear associations with intermediate phenotypes have not been described so far. To shed light on a possible influence of this chromosomal region on arterial wall integrity, we analysed associations between single nucleotide polymorphisms (SNPs) and degree of stiffness of the abdominal aorta in elderly individuals.

A total of 400 subjects, 212 men and 188 women, aged 70-88 years were included. Arterial stiffness was examined at the midpoint between the renal arteries and the aortic bifurcation. Two CAD- and aneurysm-associated SNPs (rs10757274 and rs2891168) and one T2D-associated SNP (rs1081161) within the 9p21.3 region were genotyped. Aortic compliance and distensibility coefficients were higher in carriers of the rs10757274G and rs2891168G alleles in men reflecting a decrease in aortic stiffness. Adjustment for age and mean arterial pressure had no effect on these associations. The two SNPs were not associated with intima-media thickness or lumen diameter of the abdominal aorta. There were no associations between the rs10811661 SNP and any measure of aortic stiffness.

Impaired mechanical properties of the arterial wall may explain the association between chromosome 9p21.3 polymorphisms and vascular disease.

Keyword
arterial stiffness, polymorphism, vascular disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16963 (URN)10.1111/j.1365-2796.2008.02020.x (DOI)
Note

This is the authors’ version of the following article: Hanna Björck, Toste Länne, Urban Alehagen, Karin Persson, Louise Rundkvist, A Hamsten, Ulf Dahlström and P Eriksson, Association of genetic variation on chromosome 9p21.3 and arterial stiffness, 2009, Journal of Internal Medicine, (265), 3, 373-381. which has been published in final form at: http://dx.doi.org/10.1111/j.1365-2796.2008.02020.x Copyright: Blackwell Publishing Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html

Available from: 2009-02-28 Created: 2009-02-27 Last updated: 2017-12-13Bibliographically approved
2. Gender-Specific Association of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism With Central Arterial Blood Pressure
Open this publication in new window or tab >>Gender-Specific Association of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism With Central Arterial Blood Pressure
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2011 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 24, no 7, 802-808 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND The functional plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism has previously been associated with hypertension. In recent years, central blood pressure, rather than brachial has been argued a better measure of cardiovascular damage and clinical outcome. The aim of this study was to investigate the possible influence of the 4G/5G polymorphism on central arterial blood pressure in a cohort of elderly individuals. METHODS We studied 410 individuals, 216 men and 194 women, aged 70-88. Central pressures and pulse waveforms were calculated from the radial artery pressure waveform by the use of the SphygmoCor system and a generalized transfer function. Brachial pressure was recorded using oscillometric technique (Dinamap, Critikon, Tampa, FL). PAI-1 antigen was determined in plasma. RESULTS The results showed that central pressures were higher in women carrying the PAI-1 4G/4G genotype compared to female carriers of the 5G/5G genotype, (P = 0.025, P = 0.002, and P = 0.002 for central systolic-, diastolic-, and mean arterial pressure, respectively). The association remained after adjustment for potentially confounding factors related to hypertension. No association of the PAI-1 genotype with blood pressure was found in men. Multiple regression analysis revealed an association between PAI-1 genotype and plasma PAI-1 levels (P = 0.048). CONCLUSIONS Our findings show a gender-specific association of the PAI-1 4G/5G polymorphism with central arterial blood pressure. The genotype effect was independent of other risk factors related to hypertension, suggesting that impaired fibrinolytic potential may play an important role in the development of central hypertension in women.

Place, publisher, year, edition, pages
Nature Publishing Group, 2011
Keyword
aorta; arterial stiffness; blood pressure; genetics; hypertension; pressure pulse wave
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69831 (URN)10.1038/ajh.2011.63 (DOI)000291901100014 ()
Note
Original Publication: Hanna Björck, Per Eriksson, Urban Alehagen, Rachel Debasso, Liza Ljungberg, Karin Persson, Ulf Dahlström and Toste Länne, Gender-Specific Association of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism With Central Arterial Blood Pressure, 2011, American Journal of Hypertension, (24), 7, 802-808. http://dx.doi.org/10.1038/ajh.2011.63 Copyright: Nature Publishing Group http://npg.nature.com/ Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08Bibliographically approved
3. Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor
Open this publication in new window or tab >>Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12Article in journal (Refereed) 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.

Keyword
Aorta, wall shear stress, magnetic resonance imaging, computational fluid dynamics, gene expression
National Category
Physiology Fluid Mechanics and Acoustics
Identifiers
urn:nbn:se:liu:diva-73954 (URN)10.1371/journal.pone.0052227 (DOI)000312794500119 ()
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-12-08
4. Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve
Open this publication in new window or tab >>Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve
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2013 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 91, no 1, 129-139 p.Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Springer-Verlag New York, 2013
Keyword
Aneurysm, gene expression, aorta, impaired flow, angiogenesis
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-73956 (URN)10.1007/s00109-012-0942-8 (DOI)000313077000013 ()
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-12-08

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