Abstract
Purpose: :
Animal models for Age-Related Macular Degeneration (AMD) that recapitulate the human pathology are critical for studying the mechanisms of disease onset and progression, and for the discovery and development of therapeutic interventions. Here we characterize the pathogenesis of a novel strain of mice (TJL-A) identified in a chemical mutagenesis screen which develop spontaneous and multifocal choroidal neovascularization (CNV), and investigate the underlying molecular mechanism for the CNV.
Methods: :
CNV development was evaluated by fluorescein angiography and immunostaining. Leukocyte infiltration and other inflammatory parameters were analyzed by immunohistochemistry and RT-PCR. The levels of VEGF, ICAM-1and MCP-1 in the retinal pigment epithelium (RPE)-choroid complex were examined by ELISA.
Results: :
Several neovascular tufts originated from choroid in the mid-periphery of the fundus were first detected between P10 and P15 mutants. The CNV lesions developed subretinally, increased in number with age, and the number of CNV peaked at ~ 25 per eye at P30. Additionally, the CNV anastomosed with the retinal vasculature by P25. The development of each individual CNV lesion was accompanied, and possibly preceded by F4/80 positive macrophage infiltration. In aging mice (>P60), Bruch’s membrane was thickened, CNV lesions became highly fenestrated and they were enveloped by RPE and fibroblastic cells, reminiscent of fibrosis in human neovascular AMD. VEGF, ICAM-1 and MCP-1 levels in the RPE-choroid complex were significantly (P < 0.05) higher in TJL-A mice than in age-matched controls and pharmacological blockade suggested a role for VEGF signaling in the development of CNV.
Conclusions: :
TJL-A mice develop spontaneous and multifocal subretinal CNV lesions which mimic human disease. The spontaneous and progressive nature of this model should allow us to address the pathogenic alterations that precede the onset of CNV, especially the role of inflammation, which is difficult to judge following the intense injury induced in laser-burn CNV models.
Keywords: choroid: neovascularization • age-related macular degeneration