Noninvasive Magnetic Resonance Imaging Evaluation of Endothelial Permeability in Murine Atherosclerosis Using an Albumin-Binding Contrast Agent

Abstract

Background-Endothelial dysfunction promotes atherosclerosis and precedes acute cardiovascular events. We investigated whether in vivo magnetic resonance imaging with the use of an albumin-binding contrast agent, gadofosveset, could detect endothelial damage associated with atherosclerosis in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice. Furthermore, we tested whether magnetic resonance imaging could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine. Methods and Results-ApoEϪ/Ϫ mice were imaged at 4, 8, and 12 weeks after commencement of a high-fat diet. Statin-treated ApoE Ϫ/Ϫ mice were scanned after 12 weeks of a high-fat diet. Wild-type mice were imaged before and 48 hours after injection of Russell's viper venom, an endothelial toxin. Delayed enhancement magnetic resonance imaging and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R 1 ) with progression of atherosclerosis in ApoE (R 1 ϭ3.0Ϯ0.65) mice showed less enhancement. Uptake of gadofosveset correlated with Evans blue staining, morphological changes of endothelial cells, and widening of the cell-cell junctions, suggesting that uptake occurs in regions of increased vascular permeability. Endothelial-dependent vasomotor responses showed vasoconstriction of the arteries of the ApoE Ϫ/Ϫ (Ϫ22.22Ϯ7.95%) and Russell's viper venom-injected (Ϫ10.37Ϯ17.60%) mice compared with wild-type mice (32.45Ϯ12.35%). Statin treatment improved endothelium morphology and function (Ϫ8.12Ϯ8.22%). Conclusions-We demonstrate the noninvasive assessment of endothelial permeability and function with the use of an albumin-binding magnetic resonance contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim to restore the endothelium. (Circulation. 2012;126:707-719.)Key Words: atherosclerosis Ⅲ endothelial dysfunction Ⅲ gadofosveset Ⅲ magnetic resonance imaging Ⅲ permeability A therosclerosis is a chronic disease of the vessels and a major cause of death in Western societies. Dysfunction of the vascular endothelium triggers leukocyte transmigration, platelet activation, smooth muscle cell proliferation, and vasoconstriction, which collectively promote the development of atherosclerosis. 1 Additionally, damaged endothelium can precipitate the complications of atherosclerosis through vasospasm and thrombosis, causing life-threatening cardiovascular events. Clinical Perspective on p 719Transport across the normal endothelium occurs between endothelial cells (ECs) (intercellular pathway) and/or through the ECs (transcytosis). Intercellular junctions with a diameter of Ϸ2 nm allow transport of small water-soluble molecules up to that diameter, 2 whereas breaks in the tight junctions with a diameter of Ϸ20 nm 3,4 accommodate the influx of albumin (diameter of Ϸ6 nm) and Evans blue dye (EBD). At the molecular level, oxidized low-density lipoprotein (1) decreases...

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