Abstract 4874: Vascular Endothelial Barrier Compromise in Advanced Atherosclerosis: Novel in vivo Animal Models and Nanoparticle Characterization Methods
To elucidate the functional consequences of advanced atherosclerosis on the vascular endothelial barrier, 8 NZW rabbits were fed a high fat diet for 9 –12 months (cholesterol: 1200 –1700 mg/dl). Control animals comprised 3 month-old rabbits on high fat or normal chow diets. Fluorescent perfluorocarbon-core nanoparticles (NP: ~250 nm) were given i.v. (2 ml/kg) and circulated for 1, 12, or 24 hours in selected animals. The aorta was then excised, imaged ex vivo with 12T MRI (1H and 19F) and whole mount fluorescence scanning, then fixed for histological and TEM/SEM analysis.
Results: 6/8 of the older atherosclerotic rabbits exhibited massive penetration and persistence of NP into the intimal plaques extending upwards toward the IM junction. Most NP situated in the extracellular matrix in regions that co-stained for glycosaminoglycans and smooth muscle cell actin. Fewer NP penetrated plaques after 1 hour
as compared with 12
or 24 hours, and even larger NP could be observed intact at high power
Spin-dried SEM samples revealed extensive cholesterol crystal deposition
penetrating the plaque endothelium.
19F MRI/MRS revealed the presence of fluorinated NP core elements confirming the presence of intact NP. The 3 month fed animals exhibited far less NP penetration.
Conclusion: These data suggest that disruption of the endothelial barrier in older atherosclerotic rabbits is a consequence of rapid (<1 hr) passive (non receptor-mediated) diffusion and trapping of 19F-detectable NP in plaque interstitium. If demonstrable in humans, this previously unrecognized mechanism for blood-intima communication could contribute to plaque vulnerability and disruption.