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

Akhtar, R; Cruickshank, JK; Zhao, X; Walton, LA; Gardiner, NJ; Barrett, SD; Graham, HK; Derby, B; Sherratt, MJ

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.

Citation

Akhtar, R., Cruickshank, J., Zhao, X., Walton, L., Gardiner, N., Barrett, S., …Sherratt, M. (2014). Localized micro- and nano-scale remodelling in the diabetic aorta. Acta biomaterialia, 10(11), 4843-4851. https://doi.org/10.1016/j.actbio.2014.07.001

• Journal Article Type: Article
• Acceptance Date: Jul 1, 2014
• Online Publication Date: Jul 8, 2014
• Publication Date: Nov 1, 2014
• Deposit Date: Jul 20, 2017
• Publicly Available Date: Jul 20, 2017
• Journal: Acta Biomaterialia
• Print ISSN: 1742-7061
• Publisher: Elsevier
• Volume: 10
• Issue: 11
• Pages: 4843-4851
• DOI: https://doi.org/10.1016/j.actbio.2014.07.001
• Publisher URL: http://dx.doi.org/10.1016/j.actbio.2014.07.001
• Related Public URLs: https://www.journals.elsevier.com/acta-biomaterialia
• Additional Information: Funders : British Heart Foundation;Wellcome Trust;Age UK;Engineering and Physical Sciences Research Council (EPSRC);Medical Research Council (MRC); Grant Number: FS/08/036/25364; Grant Number: WT085981AIA; Grant Number: 266; Grant Number: EP/J501487/1; Grant Number: G1001398