Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: implications for age-related macular degeneration
Open accessAbstract
Choroidal neovascularization (CNV), the advanced stage of age-related macular degeneration (AMD), accounts for >80% of vision loss in AMD. Carboxyethylpyrrole (CEP) protein modifications, uniquely generated from oxidation of docosahexaenoate-containing lipids, are more abundant in Bruch's membrane from AMD eyes. We tested the hypothesis that CEP protein adducts stimulate angiogenesis and possibly contribute to CNV in AMD. Human serum albumin (HSA) or acetyl-Gly-Lys-O-methyl ester (dipeptide) were chemically modified to yield CEP-modified HSA (CEP-HSA) or CEP-dipeptide. The in vivo angiogenic properties of CEP-HSA and CEP-dipeptide were demonstrated by using the chick chorioallantoic membrane and rat corneal micropocket assays. Low picomole amounts of CEP-HSA and CEP-dipeptide stimulated neovascularization. Monoclonal anti-CEP antibody neutralized limbal vessel growth stimulated by CEP-HSA, whereas anti-VEGF antibody was found to only partially neutralize vessel growth. Subretinal injections of CEP-modified mouse serum albumin exacerbated laser-induced CNV in mice. In vitro treatments of human retinal pigment epithelial cells with CEP-dipeptide or CEP-HSA did not induce increased VEGF secretion. Overall, these results suggest that CEP-induced angiogenesis utilizes VEGF-independent pathways and that anti-CEP therapeutic modalities might be of value in limiting CNV in AMD.
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CEP is pro-angiogenic via a VEGF-independent pathway.
“CEP is also pro-angiogenic via a VEGF-independent pathway (Ebrahem et al., 2006).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Ebrahem et al., 2006
CEP-immunization exacerbates angiogenesis in mice with laser-induced breaks in Bruch's membrane.
“CEP-immunization has also been shown to exacerbate angiogenesis in mice with laser-induced breaks in Bruch’s membrane”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Ebrahem et al., 2006
The exacerbation of angiogenesis by CEP-immunization is reversible with administration of a monoclonal anti-CEP IgM antibody.
“a finding that is reversible with administration of a monoclonal anti-CEP IgM antibody”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Ebrahem et al., 2006
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- Authors
- Ebrahem, Q., Renganathan, K., Sears, J., Vasanji, A., Gu, X., Lu, L., Salomon, R. G., Crabb, J. W., & Anand-Apte, B.
- Affiliations
- Cleveland Clinic (US)
- *Cole Eye Institute and
- Case Western Reserve University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-09-05
- Volume
- 103
- Issue
- 36
- Pages
- 13480-13484
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1569188
- OpenAlex
- W1993045845
- Cited by
- 117
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 9 · 2015: 6 · 2014: 13 · 2013: 9 · 2012: 12
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Update notices
- correction (2006-10-17)
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (EY06603)
- National Eye Institute (EY014239, EY 015638, EY06603, F32EY006603, R01EY016490, EY016490, R01EY006603, R24EY015638, R01EY014239)
- National Cancer Institute (R01CA106415, CA106415)
- National Institute of General Medical Sciences (R01GM021249, GM 21249)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- protein oxidation, choroidal neovascularization, age-related macular degeneration, angiogenesis, Bruch's membrane, human serum albumin, VEGF-independent angiogenesis, retinal pigment epithelium, laser-induced CNV
- MeSH terms
- Aged, 80 and over, Allantois, Animals, Cell Line, Cells, Cultured, Chick Embryo, Child, Chorion, Dose-Response Relationship, Drug, Humans, Macular Degeneration, Mice, Inbred C57BL, Middle Aged, Oxidation-Reduction, Pigment Epithelium of Eye, Pyrroles, Serum Albumin, Bruch Membrane, Laser Coagulation, Rats, Sprague-Dawley, Neovascularization, Physiologic, Cell Culture Techniques, Choroidal Neovascularization, Vascular Endothelial Growth Factor A, Mice, Rats
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