Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers
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Uncontrolled activation of the alternative complement pathway and secretion of vascular endothelial growth factor (VEGF) are thought to be associated with age-related macular degeneration (AMD). Previously, we have shown that in RPE monolayers, oxidative-stress reduced complement inhibition on the cell surface. The resulting increased level of sublytic complement activation resulted in VEGF release, which disrupted the barrier facility of these cells as determined by transepithelial resistance (TER) measurements. Induced rather than basal VEGF release in RPE is thought to be controlled by different mechanisms, including voltage-dependent calcium channel (VDCC) activation and mitogen-activated protein kinases. Here we examined the potential intracellular links between sublytic complement activation and VEGF release in RPE cells challenged with H(2)O(2) and complement-sufficient normal human serum (NHS). Disruption of barrier function by H(2)O(2) + NHS rapidly increased Ras expression and Erk and Src phosphorylation, but had no effect on P38 phosphorylation. Either treatment alone had little effect. TER reduction could be attenuated by inhibiting Ras, Erk and Src activation, or blocking VDCC or VEGF-R2 activation, but not by inhibiting P38. Combinatorial analysis of inhibitor effects demonstrated that sublytic complement activation triggers VEGF secretion via two pathways, Src and Ras-Erk, with the latter being amplified by VEGF-R2 activation, but has no effect on constitutive VEGF secretion mediated via P38. Finally, effects on TER were directly correlated with release of VEGF; and sublytic MAC activation decreased levels of zfp36, a negative modulator of VEGF transcription, resulting in increased VEGF expression. Taken together, identifying how sublytic MAC induces VEGF expression and secretion might offer opportunities to selectively inhibit pathological VEGF release only.
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Sublytic levels of MAC have been shown to stimulate the release of growth factors from nucleated cells, including VEGF from RPE in cell culture studies.
“For example, sublytic levels of MAC have been shown to stimulate the release of growth factors from nucleated cells [99,100], including VEGF from RPE in cell culture studies [146,165].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [165]
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- Authors
- Kunchithapautham, K., & Rohrer, B.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Rohrer, Bärbel
- ORCID
- Rohrer, Bärbel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 286
- Issue
- 27
- Pages
- 23717-23724
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3129152
- OpenAlex
- W2001008864
- Cited by
- 71
- References
- 74
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 8 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 10 · 2013: 7 · 2012: 3
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 RX000444, RX000444, C06 RR015455)
- Research to Prevent Blindness
- University of South Carolina
- National Institutes of Health (1c06rr015455-01a1)
- University of Colorado Denver
- National Eye Institute (R01EY019320)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- alternative complement pathway, retinal pigment epithelium, age-related macular degeneration, oxidative stress, hydrogen peroxide, Ras/ERK signaling, Src kinase, VEGF receptor 2, ZFP36, transepithelial electrical resistance, barrier function
- MeSH terms
- Cell Line, Complement Activation, Gene Expression Regulation, Humans, Hydrogen Peroxide, Calcium Channels, Complement Membrane Attack Complex, Oxidants, ras Proteins, src-Family Kinases, Mitogen-Activated Protein Kinase Kinases, Vascular Endothelial Growth Factor A, Tristetraprolin, Retinal Pigment Epithelium
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