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Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/14787

Title: Systemic Delivery of PTK787, a VEG FReceptor Tyrosine Kinase Inhibitor, Blocks Murine RetinoVascular Development
Authors: Stella Briggs PhD
Keywords: retinal development• pathobiology • neovascularization
Issue Date: 2007
Publisher: Invest Ophthalmol Vis Sci
Abstract: Purpose:To quantitatively determine inhibition of retinal angiogenesis using PTK787 in murine retinovascular development (RVD). Methods:Mouse pups (n=4-21 /dose) were treated with PTK787 succinate (Novartis Pharma AG, Switzerland) resuspended in PBS, injected sub-cutaneously once daily on PNDO, 1,2 and 3. Doses tested were 2.5, 10,20,25,30 and 40mglkg. Vehicle control animals received PBS. On PND4, pups were euthanised, and the eyes removed for Immunohistochemistry (!HC). Antibodies against Collagen IV (Chemicon), fluorescein-labeled secondary antibodies (Molecular Probes), and fluoresceinconjugated lectin (simplicifolia bandeira) were used to detect retinal vasculature. Processed retinas were photographed using a Nikon epifluorescent microscope at 40X magnification. Digital images of the total retinal surface were captured using an ACTI image capture software (Nikon) and imported into Photoshop©, where a pre-built radial grid of eight equally spaced lines was overlaid and centered over the optic nerve. An Image Processing Tool Kit (Reindeer Graphics, Inc.) was used to measure the distance from the center of the optic nerve to the outermost blood vessel that each line crossed. The efficacy ofPTK787 or vehicle was expressed as mean radial growth (+/- S.E.M) for each experimental group. Inter-group differences were analysed by one-way analysis of variance (ANOVA). Comparisons of experimental arms between several experiments (each with its own negative control) were analyzed by the repeated ANOV A. Pairwise comparisons of individual doses against control (in the final IV, using a pre-built radial grid overlay to measure vessel growth from the optic nerve head. Up to eight measurements were obtained per eye. Results: Sensitized pregnant females with demonstrable anti-B3 antibodies had high rates of miscarriage, and gave birth to stillborn or small pups, often with notable haemmorhage. Preliminary data suggest that new vessel growth in the retina was reduced in pups born to b3-/- mothers, and that lVlG was able to cross the placenta and lessen the inhibition of new vessel growth. This study also demonstrates the utility of evaluating retinal vascular growth as a marker of disease. Conclusions: We have demonstrated that anti-B3 integrin antibodies in female pregnant mice can I) cross the placenta causing thrombocytopenia and severe bleeding in fetuses; 2) block retinal vascular development; 3) cause miscarriage and stunted fetal growth; and, 4) that IVIG is able to lessen vascular injury. Based on these data we suggest that ophthalmic screening of retinal vascular development should be considered for newborns with unexplained haemorrhage or a suspicion ofFNAITP.
URI: http://hdl.handle.net/123456789/14787
Appears in Collections:College of Applied Medical Sciences

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