The alternative complement pathway regulates pathological angiogenesis in the retina
Open accessAbstract
A defining feature in proliferative retinopathies is the formation of pathological neovessels. In these diseases, the balance between neovessel formation and regression determines blindness, making the modulation of neovessel growth highly desirable. The role of the immune system in these retinopathies is of increasing interest, but it is not completely understood. We investigated the role of the alternative complement pathway during the formation and resolution of aberrant neovascularization. We used alternative complement pathway–deficient ( Fb –/– ) mice and age‐ and strain‐matched control mice to assess neovessel development and regression in an oxygen‐induced retinopathy (OIR) mouse model. In the control mice, we found increased transcription of Fb after OIR treatment. In the Fb –/– mice, we prepared retinal flatmounts and identified an increased number of neovessels, peaking at postnatal day 17 (P17; P =0.001). Subjecting human umbilical vein endothelial cells (HUVECs) to low oxygen, mimicking a characteristic of neovessels, decreased the expression of the complement inhibitor Cd55 . Finally, using laser capture microdissection (LCM) to isolate the neovessels after OIR, we found decreased expression of Cd55 ( P =0.005). Together, our data implicate the alternative complement pathway in facilitating neovessel clearance by down‐regulating the complement inhibitor Cd55 specifically on neovessels, allowing for their targeted removal while leaving the established vasculature intact.—Sweigard, J. H., Yanai, R., Gaissert, P., Saint‐Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., Connor, K. M. The alternative complement pathway regulates pathological angiogenesis in the retina. FASEB J . 28, 3171–3182 (2014). www.fasebj.org
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Other research has shown that inhibiting FB in a mouse model of retinal hypoxia potentially leads to increased neovascularisation, as well as increased severity and duration of retinopathy, through a reduction in endothelial cell apoptosis and increased expression of CD55.
“In contrast, other research has shown that inhibiting FB in a mouse model of retinal hypoxia potentially leads to increased neovascularisation, as well as increased severity and duration of retinopathy, through a reduction in endothelial cell apoptosis and increased expression of CD55 [163], a regulator of complement.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [163]
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- Authors
- Sweigard, J. H., Yanai, R., Gaissert, P., Saint‐Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., & Connor, K. M.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Pennsylvania (US)
- Corresponding author
- Connor, Kip M.
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2014-03-25
- Volume
- 28
- Issue
- 7
- Pages
- 3171-3182
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC4062823
- OpenAlex
- W2147633142
- Cited by
- 38
- References
- 52
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 7 · 2014: 2
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01EY022084‐01/S1, EY020633‐02, AI068730, T32EY007145, P30EY014104)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinopathy of Prematurity Studies
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- alternative complement pathway, pathological angiogenesis, retinal neovascularization, oxygen-induced retinopathy, CD55, complement inhibition, proliferative retinopathy, hypoxia, human umbilical vein endothelial cells
- MeSH terms
- Animals, Cells, Cultured, Complement Pathway, Alternative, Disease Models, Animal, Humans, Mice, Inbred C57BL, Neovascularization, Pathologic, Oxygen, Retina, Retinal Diseases, Down-Regulation, Retinal Neovascularization, Apoptosis, CD55 Antigens, Cell Proliferation, Mice, Human Umbilical Vein Endothelial Cells
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