Spontaneous CNV in a novel mutant mouse is associated with early VEGF-A-driven angiogenesis and late-stage focal edema, neural cell loss, and dysfunction.
OBJECTIVE
Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function.


METHODS
The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies.


RESULTS
The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction.


CONCLUSIONS
The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Norihiro
N
Nagai
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Pete
P
Lundh von Leithner
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Kanako
K
Izumi-Nagai
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Brett
B
Hosking
The Jackson Laboratory, Bar Harbor, Maine, United States.
Bo
B
Chang
The Jackson Laboratory, Bar Harbor, Maine, United States.
Ron
R
Hurd
GSK Ophthalmology, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Peter
P
Adamson
Genentech, Inc., South San Francisco, California, United States.
Anthony P
AP
Adamis
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Richard H
RH
Foxton
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
Yin Shan
YS
Ng
Department of Ocular Biology and Therapeutics, University College London, Institute of Ophthalmology, London, United Kingdom.
David T
DT
Shima
D000818:Animals; D002829:Choroid / Q000098:blood supply* / Q000648:ultrastructure; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004487:Edema / Q000378:metabolism* / Q000473:pathology; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009887:Ophthalmoscopy; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D012171:Retinal Vessels / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A
VEGF-A; animal models; neovascularization