Impaired Collateral Recruitment and Outward Remodeling in Experimental Diabetes

Abstract

OBJECTIVE-In this study, the effect of chronic hyperglycemia on acute ligation-induced collateral vasodilation, on monocyte chemotaxis, and on structural outward remodeling of collaterals was investigated.RESEARCH DESIGN AND METHODS-Femoral artery ligation was performed 8 weeks after alloxan or saline treatment in New Zealand White rabbits. Angiography was performed directly, 1 and 3 weeks after ligation. These angiographic recordings were used to quantify number of collaterals, lumen, and blood volume index. Reactive hyperemia response was tested by intramuscular laser Doppler measurements. Subsequently, blood was sampled from the aorta for monocyte chemotaxis.RESULTS-Ligation resulted in markedly lower acute collateral vasodilation in diabetic compared with control rabbits. Also, hyperemic vasodilatory response to local ischemia was impaired in diabetic rabbits. This difference persisted at 1 and 3 weeks after ligation, with a lower number of visible collaterals. In addition, the collateral lumen was markedly lower in diabetic rabbits after the maturation phase. Likewise, a reduced blood volume index in the region of growing collaterals was observed in diabetic animals. The monocyte migration toward vascular endothelial growth factor-A and monocyte chemotactic protein-1 was strongly reduced in diabetic rabbits.CONCLUSIONS-This study demonstrates that chronic hyperglycemia negatively affects the different phases of arteriogenesis: 1) impaired shear induced vasodilatation; 2) impaired outward collateral growth, reflected in the number of collaterals and blood volume index; and 3) inhibition of monocyte chemotaxis. Impairments were most evident in the acute phase of arteriogenesis. Therapies aimed at restoring acute collateral recruitment, such as vasodilators, may be of interest to improve collateral function in diabetes.

Diabetes Mellitus and Ischemic Diseases

“…The monocyte migration toward CCL2 is also strongly reduced in diabetic rabbits with CLI, leading to a reduced blood volume index in the region of growing collaterals. 49 Baseline P-selectin level is 4-fold higher in T2D mice compared with wild-type mice but increases minimally at day 1 after CLI, whereas P-selectin content increases ≈10-fold in wild-type mice. Immunohistology of the hindlimb skeletal muscle demonstrates severely reduced monocyte recruitment in db/db mice compared with wild-type mice.…”

Effects of prediabetes on coronary collateral circulation in patients with coronary artery disease

“…They explained the lower collateral development in hyperglycemic dogs by the fact that angiostatin showed an antiangiogenic effect. In another experimental study in rabbits with diabetes, it was shown that hyperglycemia had negative effects in all stages of collateral development [13]. There are conflicting reports about coronary collateral development in patients with diabetes.…”

VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus

“…More specifically, chronic diabetes mellitus is associated with enhanced angiogenesis in the eye (diabetic retinopathy) as well as in chronic wounds. On the other hand, chronic diabetes mellitus is associated with impaired collateral growth and arteriogenesis [15][16][17]. So far, there has been no good explanation for the angiogenic paradox in chronic diabetes mellitus.…”