title: Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization.
abstract: Increased expression of vascular endothelial cell growth factor (VEGF) in the retina is sufficient to stimulate sprouting of neovascularization 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 neovascularization from superficial and deep retinal capillaries, but not the choriocapillaris. However, retina-derived VEGF and Ang2 may not reach the choriocapillaris, because of tight junctions between retinal pigmented epithelial (RPE) cells. To eliminate this possible confounding factor, we used the human vitelliform macular dystrophy 2 (VMD2) 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. Adult mice with increased expression of VEGF in RPE cells had normal retinas and choroids with no choroidal neovascularization (CNV), but when increased expression of VEGF in RPE cells was combined with subretinal injection of a gutless adenoviral vector containing an expression construct for Ang2 (AGVAng2), CNV consistently occurred. In contrast, triple transgenic mice with induced expression of Ang2 and VEGF in RPE cells, did not develop CNV. 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.
authors.affiliation: The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oshima
authors.forename: Sachiko
authors.initials: S
authors.lastname: Oshima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nambu
authors.forename: Shu
authors.initials: S
authors.lastname: Kachi
authors.forename: Sean F
authors.initials: SF
authors.lastname: Hackett
authors.forename: Michele
authors.initials: M
authors.lastname: Melia
authors.forename: Michael
authors.initials: M
authors.lastname: Kaleko
authors.forename: Sheila
authors.initials: S
authors.lastname: Connelly
authors.forename: Noriko
authors.initials: N
authors.lastname: Esumi
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000075002:Bestrophins; D018118:Chloride Channels; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D005136:Eye Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010857:Pigment Epithelium of Eye / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D042461:Vascular Endothelial Growth Factor A; D013752:Tetracycline; D004318:Doxycycline