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

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(-/-)) mice. Furthermore, we tested whether magnetic resonance imaging could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine. ApoE(-/-) mice were imaged at 4, 8, and 12 weeks after commencement of a high-fat diet. Statin-treated ApoE(-/-) 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) [s(-1)]: R(4 weeks) 2.42±0.35, R(8 weeks) 3.45±0.54, R(12 weeks) 3.83±0.52) and Russell's viper venom-injected wild-type mice (R(1)=4.57±0.86). Conversely, wild-type (R(1)=2.15±0.34) and statin-treated ApoE(-/-) (R(1)=3.0±0.65) 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(-/-) (-22.22±7.95%) and Russell's viper venom-injected (-10.37±17.60%) mice compared with wild-type mice (32.45±12.35%). Statin treatment improved endothelium morphology and function (-8.12±8.22%). 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.