Journal article
Characterization of oxygen-induced retinopathy in mice carrying an inactivating point mutation in the catalytic site of ADAM15
Investigative ophthalmology & visual science, Vol.55(10), pp.6774-6782
09/23/2014
DOI: 10.1167/iovs.14-14472
PMCID: PMC4209716
PMID: 25249606
Abstract
Retinal neovascularization is found in diseases such as macular degeneration, diabetic retinopathy, or retinopathy of prematurity and is usually caused by alterations in oxygen supply. We have previously described that mice lacking the membrane-anchored metalloproteinase ADAM15 (a Disintegrin and Metalloprotease 15) have decreased pathological neovascularization of the retina in the oxygen-induced retinopathy (OIR) model. The main purpose of the present study was to determine the contribution of the catalytic activity of ADAM15 to OIR.
To address this question, we generated knock-in mice carrying an inactivating Glutamate to Alanine (E>A) point mutation in the catalytic site of ADAM15 (Adam15E>A mice) and subjected these animals to the OIR model and a heterotopic tumor model. Moreover, we used cell-based assays to determine whether ADAM15 can process cell surface receptors involved in angiogenesis.
We found that pathological neovascularization in the OIR model in Adam15E>A mice was comparable to that observed in wild type mice, but tumor implantation by heterotopically injected melanoma cells was reduced. In cell-based assays, overexpressed ADAM15 could process the FGFR2iiib, but was unable to process several receptors with roles in angiogenesis.
Collectively, these results suggest that the catalytic activity of ADAM15 is not crucial for its function in promoting pathological neovascularization in the mouse OIR model, most likely because of the very limited substrate repertoire of ADAM15. Instead, other noncatalytic functions of ADAM15 must be important for its role in the OIR model.
Details
- Title: Subtitle
- Characterization of oxygen-induced retinopathy in mice carrying an inactivating point mutation in the catalytic site of ADAM15
- Creators
- Thorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, United StatesCarl P Blobel - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, United States Departments of Medicine and of Physiology, Biophysics and Systems Biology, Weill-Cornell Medical College of Cornell University, New York, New York, United StatesVictor Guaiquil - The Margaret M. Dyson Vision Research Institute, Department of Ophthalmology, Weill-Cornell Medical College of Cornell University, New York, New York, United States
- Resource Type
- Journal article
- Publication Details
- Investigative ophthalmology & visual science, Vol.55(10), pp.6774-6782
- DOI
- 10.1167/iovs.14-14472
- PMID
- 25249606
- PMCID
- PMC4209716
- ISSN
- 0146-0404
- eISSN
- 1552-5783
- Grant note
- R01-EY015759 / NEI NIH HHS
- Language
- English
- Date published
- 09/23/2014
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094376202771
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