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S. Yamamoto, D. Artemov, Z. Bhujwalla, P.L. Gehlbach; Application of Magnetic Resonance Microimaging to the Quantitative Assessment of Blood-Retinal Barrier Permeability, in Transgenic Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3632.
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Purpose: Macular edema is associated with conditions that alter blood-retinal barrier (BRB) permeability. Transgenic mice with inducible expression of VEGF in the retina provide a useful model for the study of BRB permeability. Magnetic resonance (MR) microimaging extends the imaging capabilities of MRI to smaller biological applications. Here we apply MR microimaging to an evaluation of BRB permeability in transgenic mice with inducible over-expression of VEGF. Methods: The generation and characterization of rhodopsin/rtTA-TRE/VEGF transgenic mice with tetracycline inducible expression of VEGF in retinal photoreceptors has been described. Induction of VEGF was achieved by administration of doxycycline, 2 mg/ml, in drinking water for 72 hours prior to MR imaging. For MR measurements 6 animals were serially anesthetized and positioned in a plastic cradle with a 5 mm single-turn surface coil over the eye. GdDTPA contrast agent was administered by tail vein. MR imaging was performed on a GE Omega 4.7T scanner. Multi-slice sagital spin echo images with saturation recovery preparation were acquired before and for 15 min following administration of the contrast (0.1mM/kg). Images were acquired at 0,1,6 and 15 minutes. Acquisition parameters were: TE/TR= 12/700ms, ST=0.5mm, FOV=10mm, in-plane resolution of 80 micron. Following scan the eyes were removed for histological section and were stained for the presence of albumin. Results: Induction of VEGF caused characteristic fundus changes in (3/3) experimental animals that were not present in (3/3) controls. Leakage of GdDTPA was greater in 100% of experimental eyes as compared to control and corresponded to histopathological findings on albumin staining. Signal enhancement was maximal in experimental retina, vitreous and aqueous at earlier time points than corresponding control eyes. At the final time-point a 2-fold relative enhancement was apparent in the vitreous, aqueous and subretinal space while a 1.5-fold relative enhancement was present in retina compared to control. Conclusions: MR microimaging of the microstructure of the mouse eye allows quantitative assessment of kinetic differences in GdDTPA contrast movement across normal and experimentally altered BRB. MR microimaging of transgenic mice represents a novel convergence of technologies that may prove useful in pre-clinical evaluation of therapies that pertain to BRB permeability.
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