Open AccessHypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration
Author(s) -
Lijuan Zhang,
Xuan Cui,
Yangjun Han,
Karen Sophia Park,
Xiaohong Gao,
Ximei Zhang,
Zhigang Yuan,
Yong Hu,
ChunWei Hsu,
Xiaorong Li,
Alexander G. Bassuk,
Vinit B. Mahajan,
Nan-Kai Wang,
Stephen H. Tsang
Publication year - 2019
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddz159
Subject(s) - macular degeneration , neovascularization , choroidal neovascularization , retina , biology , retinal , hypoxia (environmental) , retinal degeneration , retinal pigment epithelium , pathology , angiogenesis , cancer research , ophthalmology , medicine , neuroscience , chemistry , biochemistry , organic chemistry , oxygen
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.