Inhibition of Accelerated Atherosclerosis in Vein Grafts by Placement of External Stent in ApoE*3-Leiden Transgenic Mice

Abstract

Objective-Vein grafts fail because of the development of intimal hyperplasia and accelerated atherosclerosis. Placement of an external stent around vein grafts resulted in an inhibition of intimal hyperplasia in several animal studies. Here, we assess the effects of external stenting on accelerated atherosclerosis in early vein grafts in carotid arteries in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice. Methods and Results-Venous interposition grafting was performed in apolipoprotein E*3-Leiden mice fed standard chow or a highly cholesterol-rich diet for 4 weeks. After engraftment, external stents with different inner diameters (0.4 or 0.8 mm) were placed. In unstented vein grafts in hypercholesterolemic mice, thickening up to 50 times the original thickness, with foam cell-rich lesions, calcification, and necrosis, was observed within 28 days. Key Words: atherosclerosis Ⅲ vein grafting Ⅲ external stent Ⅲ transgenic mice V ein bypass grafting remains the most common method of vascular reconstruction for bypassing obstructive arterial lesions. 1 However, aorta-coronary and peripheral vein grafts are known to have a high failure rate: 10% to 40% after 1 year and 50% to 60% after 10 years. 2 These vein grafts undergo early intimal thickening and accelerated atherosclerosis, 3-6 both of which may contribute to eventual graft failure.In patients with angiographic evidence of occlusive disease after vein grafting, atherosclerotic lesions within the graft have been demonstrated as early as 6 to 12 months after surgery. 3,4,6,7 Vein graft atherosclerotic lesions are more diffuse, concentric, and friable with a poorly developed or absent fibrous cap, whereas native vessel atheroma are proximal, focally eccentric, and nonfriable with a welldeveloped fibrous cap. 8,9 Also, compared with native atherosclerotic lesions, accelerated atherosclerotic lesions in vein grafts contain more foam cells with varying degrees of lipid accumulation and macrophage/mononuclear and inflammatory cell infiltration. 10 Compared with atherosclerosis in native arteries, this accelerated atherosclerosis in vein grafts progresses more rapidly. 11,12 Recently, Dietrich et al 13 described the fast initiation of accelerated atherosclerosis in vein grafts in hypercholesterolemic transgenic mice with the use of the very elegant, recently described technique of placing a venous interposition in the mouse carotid artery. 14 The atherosclerotic lesions observed in these murine grafts show high morphological resemblance to lesions observed in human vein grafts.A reduction of vein graft thickening or, more precisely, a reduction of neointimal thickening in vein grafts in various animal models was achieved by external stenting of grafted veins, 15-18 yielding decreased smooth muscle cell (SMC) proliferation. However, in none of these studies was the effect of external stenting on accelerated atherosclerosis in grafts determined.In the present study, we investigate the effect of external stenting on accelerated atherosclerosis, monitored as a...

Mechanical Stretch Simulates Proliferation of Venous Smooth Muscle Cells Through Activation of the Insulin-Like Growth Factor-1 Receptor

“…The report by Lardenoye et al showed that relief of this pressure with an external stent placed in vein graft model results in much less VSMC accumulation indicating that mechanical stretch of the vein will stimulate proliferation of venous VSMCs. 19 In cultured VSMCs from veins we have demonstrated that mechanical stretch (15% elongation) significantly stimulates VSMC proliferation as well as the expression of an important growth factor pathway namely, the IGF-1/IGF-1R pathway ( Figures 1, 2, and 3). Interestingly, Hu et al demonstrated that mechanical stretch can directly alter the conformation of the PDGF receptor and initiates signaling pathways that are normally used by PDGF.…”

Annexin A5 Therapy Attenuates Vascular Inflammation and Remodeling and Improves Endothelial Function in Mice

“…Apoptosis is associated with decreased plaque stability, and although AnxA5 can affect apoptosis, 13 no differences in apoptotic cell numbers detected with terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were observed at 28 days after surgery. Because apoptosis is known to occur predominantly within 14 days after surgery in this model, 28 effects on apoptosis by AnxA5 on earlier time points cannot be ruled out. Despite there being no change in apoptotic cells numbers after 28 days with AnxA5 treatment, the treatment did reduce vessel plaque instability features, such as endothelial erosion, leaky vessel formation, and severe plaque disruption, in addition to vessel wall thickening, indicating that AnxA5 treatment is effective against both vascular inflammation and the complications of vascular remodeling.…”

Reduced neointima in vein grafts following a blockage of cell recruitment from the vein and the surrounding tissue

“…The external shielding in the present study might have interfered with mechanical forces, such as shear or tensile stress, which are known to influence intimal hyperplasia [18 -20]. An external support in direct contact to the vessel wall has been shown to reduce intimal thickening in vein grafts [23,24] as well as in balloon-injured arteries [25]. However, the shielding in this study was not in close contact with the vessel wall.…”