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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\u2212\/\u2212) 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddz159","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T19:27:12Z","timestamp":1568230032000},"page":"3475-3485","source":"Crossref","is-referenced-by-count":14,"title":["Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration"],"prefix":"10.1093","volume":"28","author":[{"given":"Lijuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanxi Eye Hospital, affiliated with Shanxi Medical University. 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Fudong St. 100, Xinghualing, Taiyuan, Shanxi 030002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Wei","family":"Hsu","sequence":"first","affiliation":[{"name":"Jonas Children\u2019s Vision Care and the Bernard & Shirlee Brown Glaucoma Laboratory, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA"},{"name":"Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaorong","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute & Tianjin Medical University School of Optometry and Ophthalmology, Tianjin 300384, China, New York, NY10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander G","family":"Bassuk","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinit B","family":"Mahajan","sequence":"first","affiliation":[{"name":"Byers Eye Institute, Omics Laboratory, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94303, USA"},{"name":"Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan-Kai","family":"Wang","sequence":"first","affiliation":[{"name":"Jonas Children\u2019s Vision Care and the Bernard & Shirlee Brown Glaucoma Laboratory, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA"},{"name":"Edward S. 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Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA"},{"name":"Department of Pathology & Cell Biology, Stem Cell Initiative (CSCI), Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,9,13]]},"reference":[{"key":"2020070812441843800_ref1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.brainres.2017.07.025","article-title":"Retinal metabolism: a comparative look at energetics in the retina","volume":"1672","author":"Country","year":"2017","journal-title":"Brain Res."},{"key":"2020070812441843800_ref2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/eye.2015.254","article-title":"Spare the rods and spoil the retina: revisited","volume":"30","author":"Sivaprasad","year":"2016","journal-title":"Eye (Lond.)"},{"key":"2020070812441843800_ref3","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1136\/bjo.2004.062547","article-title":"Spare the rod and spoil the eye","volume":"89","author":"Arden","year":"2005","journal-title":"Br. 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