Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function.
The choroid in the eye provides vascular support for the retinal pigment epithelium (RPE) and the photoreceptors. Vascular endothelial growth factor (VEGF) derived from the RPE has been implicated in the physiological regulation of the choroidal vasculature, and overexpression of VEGF in this epithelium has been considered an important factor in the pathogenesis of choroidal neovascularization in age-related macular degeneration. Here, we demonstrate that RPE-derived VEGF is essential for choriocapillaris development. Conditional inactivation of VEGF expression in the RPE (in VEGFrpe-/- mice) results in the absence of choriocapillaris, occurrence of microphthalmia, and the loss of visual function. Severe abnormalities of RPE cells are already observed when VEGF expression in the RPE is only reduced (in VEGFrpe+/- mice), despite the formation of choroidal vessels at these VEGF levels. Finally, using Hif1arpe-/- mice we demonstrate that these roles of VEGF are not dependent on hypoxia-inducible factor-1alpha-mediated transcriptional regulation of VEGF expression in the RPE. Thus, hypoxia-inducible factor-1alpha-independent expression of VEGF is essential for choroid development.
Marneros
Alexander G
AG
Department of Cell Biology, Harvard Medical School, 188 Longwood Ave., Boston, MA 02115, USA. alexmarneros@hotmail.com
Fan
Jie
J
Yokoyama
Yoshihito
Y
Gerber
Hans Peter
HP
Ferrara
Napoleone
N
Crouch
Rosalie K
RK
Olsen
Bjorn R
BR
D000818:Animals; D016570:Bruch Membrane / Q000473:pathology; D002196:Capillaries / Q000254:growth & development; D002829:Choroid / Q000098:blood supply* / Q000254:growth & development* / Q000502:physiology; D004596:Electroretinography; D005123:Eye / Q000254:growth & development; D005451:Fluorescein Angiography; D015870:Gene Expression; D005786:Gene Expression Regulation; D006651:Histocytochemistry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008850:Microphthalmos / Q000235:genetics / Q000473:pathology; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology / Q000502:physiology; D010857:Pigment Epithelium of Eye / Q000473:pathology / Q000502:physiology*; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D012243:Rhodopsin / Q000032:analysis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D014786:Vision Disorders / Q000235:genetics / Q000473:pathology; D014785:Vision, Ocular
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D012243:Rhodopsin