Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow.
OBJECTIVE
Endothelial dysfunction in resistance arteries (RAs) leads to end-organ damage in type 2 diabetes. Remodelling of RAs 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 remodelling in RAs would be impaired in diabetes. Thus, we studied the structural and functional adaptation of RAs from Zucker diabetic fatty (ZDF) and lean Zucker (LZ) rats to chronic changes in flow.


RESULTS
Mesenteric RAs were alternatively ligated so that one artery was submitted to high flow (HF) and compared with normal-flow (NF) arteries located at distance. After 3 weeks, arteries were studied in vitro (n = 10 rats per group). Arterial diameter (468 vs. 394 +/- 8 microm) 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 microm) 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 with 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 overproduction in ZDF rats impaired NO-dependent dilation and HF remodelling. Indeed, a chronic treatment with tempol increased HF artery diameter and endothelium-dependent dilation in ZDF rats.


CONCLUSIONS
In type 2 diabetic rats, a chronic increase in blood flow failed to induce outward remodelling and to improve endothelium-dependent dilation, mainly because of superoxide overproduction.
Belin de Chantemèle
Eric J
EJ
INSERM U771, Angers, France.
Vessières
Emilie
E
Guihot
Anne-Laure
AL
Toutain
Bertrand
B
Maquignau
Maud
M
Loufrani
Laurent
L
Henrion
Daniel
D
D000109:Acetylcholine / Q000494:pharmacology; D000222:Adaptation, Physiological; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008026:Ligation; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D012039:Regional Blood Flow; D013113:Spin Labels; D013152:Splanchnic Circulation / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; C495537:Cav1 protein, rat; D051242:Caveolin 1; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D013113:Spin Labels; D014665:Vasodilator Agents; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011451:Prostaglandin-Endoperoxide Synthases; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000109:Acetylcholine; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin