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Noninvasive MRI Evaluation of Endothelial Permeability in Murine Atherosclerosis Using an Albumin-Binding Contrast Agent.


Circulation. 2012 Jun 29;


Authors: Phinikaridou A, Andia ME, Protti A, Indermuehle A, Shah A, Smith A, Warley A, Botnar RM


Abstract

BACKGROUND: Endothelial dysfunction promotes atherosclerosis and precedes acute cardiovascular events. We investigated whether in vivo MRI using an albumin-binding contrast agent, gadofosveset, could detect endothelial damage associated with atherosclerosis in ApoE(-/-) mice. Furthermore, we tested whether MRI could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine. METHODS AND RESULTS: ApoE(-/-) mice were imaged at 4, 8 and 12 weeks post commencement of the high-fat diet (HFD). Statin-treated ApoE(-/-) mice were scanned after 12 weeks of HFD. Wild-type (WT) mice were imaged before and 48h after injection of Russell's viper venom (RVV), an endothelial toxin. Delayed enhancement (DE) MRI and T1 mapping of the brachiocephalic artery, 30min post-injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R(1)) with progression of atherosclerosis in ApoE(-/-) [R(1) (s(-1)): R(4weeks) 2.42±0.35, R(8weeks) 3.45±0.54, R(12weeks) 3.83±0.52] and RVV-injected WT mice (R1=4.57±0.86). Conversely, WT (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 ApoE(-/-) (-22.22±7.95%) and RVV-injected (-10.37±17.60%) mice arteries compared to WT mice (32.45±12.35%). Statin treatment improved endothelium morphology and function (-8.12±8.22%). CONCLUSIONS: We demonstrate the noninvasive assessment of endothelial permeability and function using an albumin-binding MR contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim at restoring the endothelium.

PMID: 22753191 [PubMed - as supplied by publisher]