title: Adverse vascular remodelling is more sensitive than endothelial dysfunction to hyperglycaemia in diabetic rat mesenteric arteries.
abstract: Increased vascular stiffness and reduced endothelial nitric oxide (NO) bioavailability are characteristic of diabetes. Whether these are evident at a more moderate levels of hyperglycaemia has not been investigated. The objectives of this study were to examine the association between the level of glycaemia and resistance vasculature phenotype, incorporating both arterial stiffness and endothelial function. Diabetes was induced in male Sprague Dawley rats with streptozotocin (STZ; 55mg/kg i.v.) and followed for 8 weeks. One week post STZ, diabetic rats were allocated to either moderate (∼20mM blood glucose, 6-7U/insulins.c. daily) or severe hyperglycaemia (∼30mM blood glucose, 1-2U/insulins.c. daily as required). At study end, rats were anesthetized, and the mesenteric arcade was collected. Passive mechanical wall properties were assessed by pressure myography. Responses to the endothelium-dependent vasodilator acetylcholine (ACh) were assessed using wire myography. Our results demonstrated for the first time that mesenteric arteries from both moderate and severely hyperglycaemic diabetic rats exhibited outward hypertrophic remodelling and increased axial stiffness compared to arteries from non-diabetic rats. Secondly, mesenteric arteries from severely (∼30mM blood glucose), but not moderately hyperglycaemic (∼20mM blood glucose) rats exhibit a significant reduction to ACh sensitivity compared to their non-diabetic counterparts. This endothelial dysfunction was associated with significant reduction in endothelium-derived hyperpolarisation and endothelium-dependent NO-mediated relaxation. Interestingly, endothelium-derived nitroxyl (HNO)-mediated relaxation was intact. Therefore, moderate hyperglycaemia is sufficient to induce adverse structural changes in the mesenteric vasculature, but more severe hyperglycaemia is essential to cause endothelial dysfunction.
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Kahlberg
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Pharmacology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Cheng Xue
authors.initials: CX
authors.lastname: Qin
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Medicine, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Jarryd
authors.initials: J
authors.lastname: Anthonisz
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Edwina
authors.initials: E
authors.lastname: Jap
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia; Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Hooi Hooi
authors.initials: HH
authors.lastname: Ng
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Jelinic
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Parry
authors.affiliation: Cardiovascular Disease Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Pharmacology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Medicine, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: chen.leo@unimelb.edu.au.
authors.forename: Chen Huei
authors.initials: CH
authors.lastname: Leo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D066253:Vascular Remodeling; D014655:Vascular Resistance; D059289:Vascular Stiffness; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D009569:Nitric Oxide; D009589:Nitrogen Oxides; D014665:Vasodilator Agents; C039900:nitroxyl
keywords: Arterial wall stiffness; Diabetes; Differential hyperglycaemia; Endothelial function; Mesenteric artery