title: Localized micro- and nano-scale remodelling in the diabetic aorta.
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.
authors.affiliation: Centre for Materials and Structures, School of Engineering, University of Liverpool, Liverpool L69 3GH, UK. Electronic address: r.akhtar@liverpool.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Akhtar
authors.affiliation: Diabetes & Cardiovascular Medicine, Nutritional Sciences Division, King's College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Cruickshank
authors.affiliation: School of Materials, Grosvenor St, The University of Manchester, Manchester M1 7HS, UK.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, The University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Walton
authors.affiliation: Faculty of Life Sciences, AV Hill Building, Oxford Road, The University of Manchester, Manchester M13 9PT, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Gardiner
authors.affiliation: Surface Science Research Centre, Department of Physics, University of Liverpool, Liverpool, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Barrett
authors.affiliation: Institute of Inflammation and Repair, Manchester Academic and Health Sciences Centre, Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: H K
authors.initials: HK
authors.lastname: Graham
authors.affiliation: School of Materials, Grosvenor St, The University of Manchester, Manchester M1 7HS, UK.
authors.forename: B
authors.initials: B
authors.lastname: Derby
authors.affiliation: Institute of Inflammation and Repair, Manchester Academic and Health Sciences Centre, Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sherratt
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000503:physiopathology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003094:Collagen / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D000071837:Fibrillins; D018093:Gelatinases / Q000378:metabolism; D006031:Glycosylation; D008297:Male; D020894:Microfibrils / Q000648:ultrastructure; D008840:Microfilament Proteins / Q000378:metabolism; D036103:Nanotechnology; D017208:Rats, Wistar; D013016:Sound; D017540:Tunica Media / Q000473:pathology; D066253:Vascular Remodeling
chemical_list: D001786:Blood Glucose; D000071837:Fibrillins; D008840:Microfilament Proteins; D003094:Collagen; D018093:Gelatinases
keywords: Arterial stiffening; Extracellular matrix; Fibrillin microfibrils; Mechanical properties; Type 1 diabetes