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Hypoxic drive caused type 3 neovascularization in a preclinical model of exudative age-related macular degeneration
- Source :
- Hum Mol Genet
- Publication Year :
- 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.
- Subjects :
- 0301 basic medicine
Vascular Endothelial Growth Factor A
medicine.medical_specialty
Pathology
genetic structures
Biology
Neovascularization
03 medical and health sciences
chemistry.chemical_compound
Macular Degeneration
Mice
0302 clinical medicine
Genetics
medicine
Animals
Hypoxia
Molecular Biology
Erythropoietin
Genetics (clinical)
Retina
Neovascularization, Pathologic
Retinal
General Medicine
Macular degeneration
Hypoxia (medical)
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
eye diseases
Vascular endothelial growth factor A
030104 developmental biology
medicine.anatomical_structure
chemistry
030221 ophthalmology & optometry
Immunohistochemistry
Histopathology
sense organs
General Article
medicine.symptom
Subjects
Details
- ISSN :
- 14602083
- Volume :
- 28
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....8106dbd6aa8021673016c220990f6996