Noninvasive MRI monitoring of the effect of interventions on endothelial permeability in murine atherosclerosis using an albumin-binding contrast agent.
BACKGROUND
Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging (MRI) using an albumin-binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high-fat diet (HFD)-fed ApoE-/- mice.


RESULTS
ApoE-/- mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD. HFD-fed ApoE-/- mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed-enhancement MRI and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R1, s(-1)) in untreated HFD-fed ApoE-/- mice (R1 = 3.8 ± 0.52 s(-1)) compared with controls (R1 = 2.15 ± 0.34 s(-1), P < 0.001). Conversely, minocycline-treated (R1 = 2.7 ± 0.17 s(-1), P < 0.001) and ebselen-treated (R1 = 2.7 ± 0.23 s(-1), P < 0.001) ApoE-/- mice showed less vessel wall enhancement compared with untreated HFD-fed ApoE-/- mice. Mass spectroscopy showed a lower gadolinium concentration in the brachiocephalic artery of treated (minocycline = 28.5 ± 3 μmol/L, ebselen = 32.4 ± 4 μmol/L) compared with untreated HFD-fed ApoE-/- mice (191 ± 4.8 μmol/L) (P < 0.02). Both interventions resulted in a lower plaque burden as measured by delayed-enhancement MRI (minocycline = 0.14 ± 0.02 mm2, ebselen= 0.20 ± 0.09 mm2), untreated = 0.44 ± 0.01 mm2; P < 0.001) and histology (minocycline = 0.13 ± 0.05 mm2, ebselen = 0.18 ± 0.02 mm2, untreated = 0.32 ± 0.04 mm2; P < 0.002). Endothelium cells displayed fewer structural changes and smaller gap junction width in treated compared with untreated animals as seen by electron microscopy (minocycline=42.3 ± 8.4 nm, ebselen = 56.5 ± 17 nm, untreated = 2400 ± 39 nm; P < 0.001). Tissue flow cytometry of the brachiocephalic artery showed lower monocyte/macrophage content in both ebselen- and minocycline-treated mice (8.06 ± 3.2% and 7.62 ± 1.73%, respectively) compared with untreated animals (20.1 ± 2.2%) (P = 0.03), with significant attenuation of the proinflammatory Ly6Chigh subtype (untreated mice, 42.64 ± 6.1% of total monocytes; ebselen, 14.07 ± 9.5% of total monocytes; minocycline, 26.42 ± 0.6% of total monocytes).


CONCLUSIONS
We demonstrate that contrast-enhanced MRI with an albumin-binding contrast agent can be used to noninvasively monitor the effect of interventions on endothelial permeability and plaque burden. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim at restoring endothelial integrity.
Division of Imaging Science and Biomedical Engineering, King's College London, London, United Kingdom.
Alkystis
A
Phinikaridou
Marcelo E
ME
Andia
Gabriella
G
Passacquale
Albert
A
Ferro
Rene M
RM
Botnar
D000418:Albumins; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000175:diagnosis* / Q000378:metabolism*; D001393:Azoles / Q000494:pharmacology*; D003287:Contrast Media; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005682:Gadolinium; D054833:Isoindoles; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008911:Minocycline / Q000494:pharmacology*; D009942:Organometallic Compounds; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects
D000418:Albumins; D000900:Anti-Bacterial Agents; D000975:Antioxidants; D001393:Azoles; D003287:Contrast Media; D054833:Isoindoles; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; C042986:ebselen; D005682:Gadolinium; D008911:Minocycline; C109932:gadofosveset trisodium
MRI; atherosclerosis; endothelial dysfunction; gadofosveset; monocytes; permeability