PURPOSE.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.Keywords: animal models, neovascularization, VEGF-A T he transformative nature of recent therapeutic developments for neovascular age-related macular degeneration (nAMD) has triggered an exponential increase in ophthalmic drug development efforts over the past decade. 1 The most prevalent assay used to benchmark potential new nAMD compounds and therapeutic strategies is rodent laser-induced choroidal neovascularization (lCNV). [2][3][4][5] This model is used to assess antiangiogenic activity and the ability to reduce vascular permeability, two hallmarks of nAMD. Moreover, because of the ease of imaging the posterior pole, lCNV is often used as a secondary pharmacology model during drug development for other conditions, such as cancer. However, the lCNV model has several limitations, including acute, intense laser injury to the photoreceptors, RPE, and choriocapillaris to induce angiogenesis, the accumulation of hypertrophic scar tissue, and a natural regression of the neovascularization. 6 Therefore, factors that initiate the CNV, and long-term analysis of the consequences of the neovessels to the retina, cannot be readily studied. Here we describe a novel genetic model of multifocal, bilateral spontaneous choroidal neovascularization (sCNV), which leads to early, persistent neovascular lesions that leak and lead to retinal edema, local gliosis and focal photoreceptor dysfunction, and death. Approximately 10% to 15% of the lesions will eventually anastomose with the...