O68	Early arteriogenic defects in a diabetic ischemic hindlimb model.
1J.van Golde, 2S.Vöö, 2J.Waltenberger, 1N.Schaper, 1M.Huijberts
1Department of Internal Medicine, Endocrinology, Maastricht, NL; 2Department of Cardiology, University Hospital Maastricht, Cardiovascular Research Institute Maastricht, Maastricht, NL.

Some studies suggest that impaired collateral formation contributes to the poor outcome of limb ischemia in diabetes. The mechanism of this disturbance is unclear and can include acute, early or late events in arteriogenesis. Therefore, we determined the effect of chronic hyperglycemia on acute ligation induced vasodilatation (due to the increase in shear stress), monocyte recruitment and maturation phase in arteriogenesis. Hyperglycemia was induced in New Zealand rabbits by alloxan injection; after 8 weeks unilateral a. femoralis ligation was performed. Collateral growth was subsequently quantified by longitudinal X-ray angiography of both limbs, directly (T0), one (T1) and three weeks (T2) after ligation. Monocyte migration function was determined post-mortem in all animals using a modified Boyden chamber using VEGF-A (1 ng/ml) and MCP-1 (30 ng/ml) as chemoattractants. Mean blood glucose levels was 6.1 ± 1.1 in controls (n=6) and 29.4 ± 4.2 mmol/l in diabetic (n=6) rabbits, while no differences in blood lipids were observed. Angiographic results are depicted in the graph. Ligation resulted at T0 in markedly lower acute vessel recruitment in diabetic compared to the control rabbits (p=0.02), this difference persisted at T1 and T2, with lower number of visible collaterals (p=0.038 and p=0.002, respectively). In particular, the percentage of vessels larger than 400 µm was lower in diabetic rabbits at both time points (data not shown). Likewise, the monocyte migration towards VEGF-A and MCP-1 was reduced with more than 2-fold in diabetic rabbits vs. controls (p=0.019 and p=0.006, respectively). This study demonstrates that chronic hyperglycemia negatively affects the different phases of arteriogenesis: a) impaired shear induced vasodilatation, b) inhibition of monocyte migration and c) impaired outward collateral growth. The most marked abnormalities were observed in the initiation phase of collateral growth, suggesting that impaired shear stress sensing or signal transduction could be a fundamental defect in the impaired arteriogenesis in diabetes.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.