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Y. Oshima, S. Oshima, H. Nambu, S. Kachi, S.F. Hackett, M. Kaleko, S. Connelly, N. Esumi, D.J. Zack, P.A. Campochiaro; Increased Expression of VEGF in Retinal Pigmented Epithelial (RPE) Cells is Not Sufficient to Cause Choroidal Neovascularization (CNV) . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2229.
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Purpose: Increased expression of vascular endothelial growth factor (VEGF) in the retina is sufficient to stimulate sprouting of neovascularization (NV) from the deep capillary bed of the retina, but not the superficial retinal capillaries or the choriocapillaris. Coexpression of VEGF and angiopoietin 2 (Ang2) results in sprouting of NV from superficial and deep retinal capillaries, but not the choriocapillaris. In this study, we used the human VMD2 (vitelliform macular dystrophy 2) promoter, an RPE–specific promoter, combined with the tetracycline–inducible promoter system, to generate double transgenic mice with inducible expression of VEGF in RPE cells. Methods: Double transgenic mice with doxycycline–inducible expression of VEGF in RPE cells (VMD2/rtTA–TRE/VEGF mice) and triple transgenics (VMD2/rtTA–TRE/VEGF–TRE/Ang2) with inducible expression of both VEGF and Ang2 in RPE cells were generated. Subretinal injections of gutless adenoviral vectors expressing Ang2 (AGVAng2) were performed as previously described. Results: Adult mice with increased expression of VEGF in RPE cells had normal retinas and choroids with no CNV, but when increased expression of VEGF in RPE cells was combined with subretinal injection of AGVAng2, CNV consistently occurred. In contrast, triple transgenic mice with induced expression of Ang2 and VEGF in RPE cells, did not develop CNV. Conclusions: These data suggest that increased expression of VEGF and/or Ang2 in RPE cells is not sufficient to cause CNV unless it is combined with a subretinal injection of a gutless adenoviral vector, which is likely to perturb RPE cells. These data also suggest that the effects of angiogenic proteins may vary among vascular beds, even those that are closely related, and therefore generalizations should be avoided.
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