| 1. |
- Björck, Hanna, 1979-
(author)
-
Vessel wall integrity : influence of genetics and flow
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- 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.
|
|
| 2. |
- Andersson, Jonas, 1969-
(author)
-
Adipose tissue as an active organ : blood flow regulation and tissue-specific glucocorticoid metabolism
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF. Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women. Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups. Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.
|
|
