Localized micro- and nano-scale remodelling in the diabetic aorta

Akhtar, R, Cruickshank, JK, Zhao, X, Walton, LA ORCID: https://orcid.org/0000-0002-8651-7443, Gardiner, NJ, Barrett, SD, Graham, HK, Derby, B and Sherratt, MJ 2014, 'Localized micro- and nano-scale remodelling in the diabetic aorta' , Acta Biomaterialia, 10 (11) , pp. 4843-4851.

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Abstract

Diabetes is strongly associated with cardiovascular disease, but the mechanisms, structural and biomechanical consequences of aberrant blood vessel remodelling remain poorly defined. Using an experimental (streptozotocin, STZ) rat model of diabetes, we hypothesized that diabetes enhances extracellular protease activity in the aorta and induces morphological, compositional and localized micromechanical tissue remodelling. We found that the medial aortic layer underwent significant thickening in diabetic animals but without significant changes in collagen or elastin (abundance). Scanning acoustic microscopy demonstrated that such tissue remodelling was associated with a significant decrease in acoustic wave speed (an indicator of reduced material stiffness) in the inter-lamellar spaces of the vessel wall. This index of decreased stiffness was also linked to increased extracellular protease activity (assessed by semi-quantitative in situ gelatin zymography). Such a proteolytically active environment may affect the macromolecular structure of long-lived extracellular matrix molecules. To test this hypothesis, we also characterized the effects of diabetes on the ultrastructure of an important elastic fibre component: the fibrillin microfibril. Using size exclusion chromatography and atomic force microscopy, we isolated and imaged microfibrils from both healthy and diabetic aortas. Microfibrils derived from diabetic tissues were fragmented, morphologically disrupted and weakened (as assessed following molecular combing). These structural and functional abnormalities were not replicated by in vitro glycation. Our data suggest that proteolysis may be a key driver of localized mechanical change in the inter-lamellar space of diabetic rat aortas and that structural proteins (such as fibrillin microfbrils) may be biomarkers of diabetes induced damage.

Item Type:	Article
Schools:	Schools > School of Health and Society > Centre for Health Sciences Research
Journal or Publication Title:	Acta Biomaterialia
Publisher:	Elsevier
ISSN:	1742-7061
Related URLs:	Publication
Funders:	British Heart Foundation, Wellcome Trust, Age UK, Engineering and Physical Sciences Research Council (EPSRC), Medical Research Council (MRC)
Depositing User:	LA Walton
Date Deposited:	20 Jul 2017 14:56
Last Modified:	15 Feb 2022 22:16
URI:	https://usir.salford.ac.uk/id/eprint/43110

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