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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn334
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow

Eric J. Belin de Chantemèle, Ph.D., Emilie Vessières, M.S., Anne-Laure Guihot, B.Sc, Bertrand Toutain, B.Sc., Maud Maquignau, B.Sc., Laurent Loufrani, Ph.D. and Daniel Henrion, Ph.D.

INSERM U771, Angers, France; CNRS UMR 6214, Angers, France; Université d'Angers, France.

Address for Correspondence: Dr. Daniel Henrion, Pharm.D., Ph.D. Dept of Integrated Neurovascular Biology, UMR CNRS 6214 - INSERM 771 Faculté de Médecine, 49045 Angers, FRANCE tel: 332 41 73 58 45 fax: 332 41 73 58 95 E-mail: daniel.henrion{at}univ-angers.fr

Aims: Endothelial dysfunction in resistance arteries (RA) leads to end organ damage in type 2 diabetes. Remodeling of RA in response to chronic increases in blood flow depends on the integrity of the endothelium. Since type 2 diabetes impairs endothelial sensitivity to flow and increases oxidative stress, we hypothesized that flow-induced remodeling in RA would be impaired in diabetes. Thus, we studied the structural and functional adaptation of RA from Zucker diabetic fatty (ZDF) and lean (LZ) rats to chronic changes in flow.

Methods: Mesenteric RA were alternatively ligated so that one artery was submitted to high flow (HF) and compared to normal flow (NF) arteries located at distance. After 3 weeks, arteries were studied in vitro (n= 10 rats per group).

Results: Arterial diameter (468 vs 394 ± 8 µm) and endothelial (acetylcholine)-dependent dilation (91 ± 8 vs 75 ± 6% dilation) were higher in HF than in NF arteries in LZ rats. In ZDF rats, diameter (396 ± 9 vs 440 ± 17 µm) and acetylcholine-mediated dilation (42 ± 8 vs 75 ± 7%) were lower in HF than in NF arteries. Nevertheless, endothelial NO synthase and NADP(H) oxidase subunits (gp91, p67) expression level and superoxide production (dihydroethidium staining) were higher in HF than in NF arteries in both strains, suggesting an efficient flow-sensing process in ZDF rats. In ZDF rats basal oxidative stress was higher compared to LZ rats: dihydroethidium staining was higher in NF and HF arteries from ZDF rats, and acetylcholine-mediated dilation was improved by an acute antioxidant (tempol) in NF and HF arteries from ZDF rats. Thus, superoxide over-production in ZDF rats impaired NO-dependent dilation and HF remodeling. Indeed, a chronic treatment with tempol increased HF artery diameter and endothelium-dependent dilation in ZDF rats.

Conclusion: In type 2 diabetic rats a chronic increase in blood flow failed to induce outward remodeling and to improve endothelium-dependent dilation, mainly because of superoxide overproduction.

Time for primary review: 20 Days


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