No abstract

We investigated the effects of sequential and prolonged exposure to high and low wall shear stress on arterial remodeling using a rabbit arteriovenous fistula (AVF) model. Blood flow was increased by approximately 17-fold to 20-fold when the AVF was open, and returned to normal when the AVF was occluded. Repeated opening and closing of the AVF resulted in sequential exposure of the artery to high and low wall shear stress. High flow and high wall shear stress induced arterial dilatation, elongation, and tortuosity, without intimal thickening. The common carotid artery was elongated 37% after 4 weeks of high flow, and was shortened 10% after 6 weeks of normal flow. Subsequent cycles of high flow induced less elongation, with less shortening after return to normal flow. Enlargement of the distal segment was more dramatic than in the proximal segment, despite exposure to the same volume of flow and the same initial high wall shear stress after creation of the AVF. The distal carotid segment enlarged more than did the proximal segment during each exposure to high flow. In segments of carotid artery exposed to low wall shear stress (<5 dynes/cm(2)) intimal thickening developed. These changes were maximal in the distal carotid segment, just before the AVF. Each cycle of low wall shear stress induced intimal thickening accompanied by medial hyperplasia. Intimal thickening was inhibited during periods of high flow when wall shear stress was high. Three cycles of flow alteration induced three layers of intimal thickening in the distal arterial segment, two layers of intimal thickening in the middle segment, and one layer of intimal thickening in the proximal segment. Long-term exposure to low wall shear stress induced severe intimal thickening and medial hyperplasia in different segments. Thus the response of the carotid artery afferent to an AVF varies along the length of the artery, with maximum enlargement, elongation, and tortuosity in the distal segment, just proximal to the AVF. Similarly, intimal thickening in response to low wall shear stress is maximal in the distal carotid artery. It appears that intimal thickening is related to local levels of low wall shear stress, and occurs when wall shear stress chronically falls to less than 5 dynes/cm(2).

Objective Diabetes mellitus (DM) is associated with reduced progression of abdominal aortic aneurysm (AAA) disease. Mechanisms responsible for this negative association remain unknown. We created AAAs in hyperglycemic mice to examine the influence of serum glucose concentration on experimental aneurysm progression. Methods Aortic aneurysms were induced in hyperglycemic (DM) and normoglycemic models by using intra-aortic porcine pancreatic elastase (PPE) infusion in C57BL/6 mice or by systemic infusion of angiotensin II (ANG) in apolipoprotein E-deficient (ApoE−/−) mice, respectively. In an additional DM cohort, insulin therapy was initiated after aneurysm induction. Aneurysmal aortic enlargement progression was monitored with serial transabdominal ultrasound measurements. At sacrifice, AAA cellularity and proteolytic activity were evaluated by immunohistochemistry and substrate zymography, respectively. Influences of serum glucose levels on macrophage migration were examined in separate models of thioglycollate-induced murine peritonitis. Results At 14 days after PPE infusion, AAA enlargement in hyperglycemic mice (serum glucose ≥ 300 mg/dL) was less than that in euglycemic mice (PPE-DM: 54% ± 19% vs PPE: 84% ± 24%, P < .0001). PPE-DM mice also demonstrated reduced aortic mural macrophage infiltration (145 ± 87 vs 253 ±119 cells/cross-sectional area, P = .0325), elastolysis (% residual elastin: 20% ± 7% vs 12% ± 6%, P = .0209), and neovascularization (12 ± 8 vs 20 ± 6 vessels/high powered field, P = .0229) compared with PPE mice. Hyperglycemia limited AAA enlargement after ANG infusion in ApoE−/− mice (ANG-DM: 38% ± 12% vs ANG: 61% ± 37% at day 28). Peritoneal macrophage production was reduced in response to thioglycollate stimulation in hyperglycemic mice, with limited augmentation noted in response to vascular endothelial growth factor administration. Insulin therapy reduced serum glucose levels and was associated with AAA enlargement rates intermediate between euglycemic and hyperglycemic mice (PPE: 1.21 ± 0.14 mm vs PPE-DM: 1.00 ± 0.04 mm vs PPE-DM + insulin: 1.14 ± 0.05 mm). Conclusions Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease. Clinical Relevance This report provides mechanistic insight into prior population-based clinical studies identifying a negative association between diabetes mellitus and abdominal aortic aneurysm (AAA). The inhibitory effects of hyperglycemia on aneurysm development are examined independent of other AAA risk factors. Further investigations into these or related mechanisms may accelerate the development of effective medical strategies to suppress progression of AAA disease.