Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration

Alexander G Bassuk; Lijuan Zhang; Xuan Cui; Vinit B Mahajan; Yangjun Han; Karen Sophia Park; Xiaohong Gao; Ximei Zhang; Zhigang Yuan; Yong Hu; Chun-Wei Hsu; Xiaorong Li; Nan-Kai Wang; Stephen H Tsang

doi:10.1093/hmg/ddz159

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Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration

Journal article

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Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration

Alexander G Bassuk, Lijuan Zhang, Xuan Cui, Vinit B Mahajan, Yangjun Han, Karen Sophia Park, Xiaohong Gao, Ximei Zhang, Zhigang Yuan, Yong Hu, …

Human molecular genetics, Vol.28(20), pp.3475-3485

10/15/2019

DOI: 10.1093/hmg/ddz159

PMID: 31518400

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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.

Macular Degeneration - metabolism

Animals

Hypoxia - pathology

Hypoxia-Inducible Factor 1, alpha Subunit - metabolism

Mice

Neovascularization, Pathologic - metabolism

Vascular Endothelial Growth Factor A - metabolism

Erythropoietin - metabolism

Hypoxia - metabolism

Macular Degeneration - pathology

Neovascularization, Pathologic - pathology

Details

Title: Subtitle: Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration
Creators: Alexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
Lijuan Zhang - Shanxi Eye Hospital, affiliated with Shanxi Medical University. Fudong St. 100, Xinghualing, Taiyuan, Shanxi 030002, China
Xuan Cui - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Vinit B Mahajan - Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
Yangjun Han - Shanxi Cardiovascular Disease Hospital, Yifen street 18, Wanbailin, Taiyuan, Shanxi 030024, China
Karen Sophia Park - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Xiaohong Gao - Shanxi Eye Hospital, affiliated with Shanxi Medical University. Fudong St. 100, Xinghualing, Taiyuan, Shanxi 030002, China
Ximei Zhang - Shanxi Eye Hospital, affiliated with Shanxi Medical University. Fudong St. 100, Xinghualing, Taiyuan, Shanxi 030002, China
Zhigang Yuan - Shanxi Eye Hospital, affiliated with Shanxi Medical University. Fudong St. 100, Xinghualing, Taiyuan, Shanxi 030002, China
Yong Hu - Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, China
Chun-Wei Hsu - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Xiaorong Li - 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
Nan-Kai Wang - Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032, USA
Stephen H Tsang - 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
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.28(20), pp.3475-3485
DOI: 10.1093/hmg/ddz159
PMID: 31518400
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81500750, P30EY019007, R01EY018213, R01EY024698; DOI: 10.13039/501100009581, name: Shaanxi Health and Family Planning Commission, award: 2018088; DOI: 10.13039/100000054, name: National Cancer Institute, award: 5P30CA013696; DOI: 10.13039/100012636, name: New York State Stem Cell Science, award: C32590GG; DOI: 10.13039/100001116, name: Foundation Fighting Blindness, award: TA-NMT-0116-0692-COLU; name: Schneeweiss Stem Cell, award: C029572; DOI: 10.13039/100000002, name: National Institutes of Health
Language: English
Date published: 10/15/2019
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984070404602771

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