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Title: The influence of caveolin-1 and ageing on resistance artery structure and function
Author: Hausman, Natasha L.
ISNI:       0000 0004 2688 2566
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2009
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Ageing is a risk factor for cardiovascular disease (CVD) and involves changes in the function and structure of resistance arteries. Membrane invaginations called caveolae are involved in cell signalling regulation, and can influence the active and passive properties of resistance arteries. Changes in caveolae and their structural protein caveolin-l have been implicated in CVD, therefore the role of caveolin-l in vascular ageing was investigated. Isolated resistance arteries from 3 and 12 month old wild-type (WT) and caveolin-l knock-out (KO) mice were examined. Mesenteric and femoral arteries mounted on a pressure myograph were exposed to a high potassium solution (KPSS), noradrenaline (NA), acetylcholine (ACh) and sodium nitroprusside. Concentration-response curves to NA and ACh were also performed in the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine. Pressure steps in calcium-free solution allowed investigation of passive vessel properties. Mesenteric arteries from 12 month old WT mice exhibited reduced constriction to NA and KPSS, increased nitric oxide (NO) availability and outward hypertrophic remodelling when compared to those from 3 month old WT mice. Similar changes were observed in arteries from 3 month old caveolin- 1 KO mice compared to age-matched WT controls. There was no age-related change in the response of vessels from caveolin-l KO mice to NA, and no significant role for NO in mesenteric arteries from 12 month old caveolin-l KO mice. However, femoral arteries from 12 month old caveolin-l KO mice dilated more to ACh than WT controls, in line with increased NO availability. This would be .consistent with increased endothelial nitric oxide synthase (eNOS) activity in the absence of inhibition by caveolin-l. Increased NO production in femoral arteries from caveolin-l KO mice was also associated with reduced distensibility, which may act to maintain blood pressure. Vessels from 3 month old female WT mice constricted less to NA than vessels from age-matched male mice. Caveolin-l ablation abolished this gender difference. The effects of caveolin-l ablation on vessels from 3 month old male mice were in line with the effects of ageing in male WT mice, suggesting premature vascular ageing in young male caveolin-l KO mice. Ageing in female WT mice and caveolin-l ablation in 3 month old female mice did not have the same effects, suggesting oestrogens may modify vascular ageing. Gender differences in the effects of ageing on vessels from caveolin-l KO mice were also observed. There was no age-related decrease in NO availability in vessels from female mice, in contrast to males. Vessels from female caveolin-l KO mice underwent age-related outward hypertrophic remodelling, in contrast to atrophy of vessels in male mice. This may reflect the role of oestrogens in regulating vascular function and structure. Caveolae appear to be involved in mediating the effects of vascular ageing and gender differences in vascular responses. Interactions between oestrogens, eNOS and caveolae may therefore be important in long-term regulation of vascular function and structure. As vascular ageing may contribute to development of CVD, and there are gender differences in the incidence of CVD, the role of caveolae may be an important consideration in the design of future therapeutic treatments.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available