The role of glycosaminoglycans in vascular stiffness and non-osmotic sodium storage

The goal of this thesis was to investigate the interplay between sodium, glycosaminoglycans, vascular stiffness, and hypertension. In contrast to the traditional view of salt-dependent hypertension, recent studies have found that sodium accumulation can occur without commensurate fluid retention. Researchers hypothesise that this sodium is stored non-osmotically via association with negatively charged glycosaminoglycans (GAGs) in the extracellular matrix. The interaction of sodium and GAGs, the influence of sodium on GAG production, and the ability of GAGs to affect vascular stiffness are of key interest. This thesis first investigates the link between hypertension, vascular stiffness, and GAGs in ex vivo human aortae. Aortae from hypertensive donors were found to be stiffer than normotensive controls even after controlling for both pressure and age, a novel finding in humans. In these aortae, hypertension was associated with GAG remodelling, but not with changes in total GAG content. Next, an interventional rat study is presented to examine the effects of dietary salt on vascular stiffness and GAGs, and to distinguish between salt-dependent and blood pressure-dependent effects. In vivo vascular stiffness was found to be salt-dependent but pressure-independent, with ex vivo stiffness unaffected by salt. Ex vivo stiffness was also independent of aortic GAG content, similar to the human aortae described previously. GAG content in the skin was both salt-dependent and pressure-dependent. Finally, this thesis closes with an interventional study in humans. This study was designed to examine the effects of diuretic-induced salt loss on sodium storage, GAGs, and haemodynamics. An eight-day diuretic course corresponded to a ~10% reduction in skin sodium content, without associated water loss or cardiovascular changes. GAG mRNA expression was decreased in the skin, suggesting reduced GAG content. Pilot work from this study supports the use of 23Na MRI as a non-invasive measurement of skin sodium, but only for pre- vs post-treatment comparisons rather than absolute quantification. In conclusion, this thesis demonstrates that both salt and blood pressure influence GAG accumulation and distribution, but that GAGs do not directly affect vascular stiffness. However, GAGs do play a direct role in osmotically inactive sodium storage, which may modulate development of hypertension.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2018

Author dc:creator

• Connolly, Kathleen

Advisors dc:contributor.advisor

• Wilkinson, Ian
• McEneiry, Carmel

• Glycosaminoglycans
• Vascular stiffness
• Hypertension
• Non-osmotic sodium storage
• Skin
• Sodium
• Aorta

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d8f162b5-0aa5-40e4-9151-ec2131b0c06a/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.25349

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/278023