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Hypoxic drive caused Type 3 neovascularization in a preclinical model of exudative age-related macular degeneration. Human molecular genetics Zhang, L., Cui, X., Han, Y., Park, K. S., Gao, X., Zhang, X., Yuan, Z., Hu, Y., Hsu, C., Li, X., Bassuk, A. G., Mahajan, V. B., Wang, N., Tsang, S. H. 2019

Abstract

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives Type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages, and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.

View details for DOI 10.1093/hmg/ddz159

View details for PubMedID 31518400