Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration

Shemin Zeng; S Scott Whitmore; Elliott H Sohn; Megan J Riker; Luke A Wiley; Todd E Scheetz; Edwin M Stone; Budd A Tucker; Robert F Mullins

doi:10.1002/path.4669

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Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration

Journal article

Open access

Peer reviewed

Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration

Shemin Zeng, S Scott Whitmore, Elliott H Sohn, Megan J Riker, Luke A Wiley, Todd E Scheetz, Edwin M Stone, Budd A Tucker and Robert F Mullins

The Journal of pathology, Vol.238(3), pp.446-456

02/2016

DOI: 10.1002/path.4669

PMCID: PMC4900182

PMID: 26564985

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http://doi.org/10.1002/path.4669View

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Abstract

Age-related macular degeneration (AMD) is a common, blinding disease of the elderly in which macular photoreceptor cells, retinal pigment epithelium and choriocapillaris endothelial cells ultimately degenerate. Recent studies have found that degeneration of the choriocapillaris occurs early in this disease and that endothelial cell drop-out is concomitant with increased deposition of the complement membrane attack complex (MAC) at the choroidal endothelium. However, the impact of MAC injury to choroidal endothelial cells is poorly understood. To model this event in vitro, and to study the downstream consequences of MAC injury, endothelial cells were exposed to complement from human serum, compared to heat-inactivated serum, which lacks complement components. Cells exposed to complement components in human serum showed increased labelling with antibodies directed against the MAC, time- and dose-dependent cell death, as assessed by lactate dehydrogenase assay and increased permeability. RNA-Seq analysis following complement injury revealed increased expression of genes associated with angiogenesis including matrix metalloproteinase (MMP)-3 and -9, and VEGF-A. The MAC-induced increase in MMP9 RNA expression was validated using C5-depleted serum compared to C5-reconstituted serum. Increased levels of MMP9 were also established, using western blot and zymography. These data suggest that, in addition to cell lysis, complement attack on choroidal endothelial cells promotes an angiogenic phenotype in surviving cells.

Macular Degeneration - etiology

Up-Regulation

Complement System Proteins - pharmacology

Dose-Response Relationship, Immunologic

Antibodies - metabolism

Macular Degeneration - immunology

Humans

Cells, Cultured

Choroid - blood supply

Male

Matrix Metalloproteinase 3 - metabolism

Vascular Endothelial Growth Factor A - metabolism

Complement Membrane Attack Complex - immunology

Endothelial Cells - immunology

Matrix Metalloproteinase 9 - metabolism

Cell Death - physiology

Aged, 80 and over

Choroid - immunology

Female

Aged

Complement Activation - physiology

Macular Degeneration - pathology

Details

Title: Subtitle: Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration
Creators: Shemin Zeng - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
S Scott Whitmore - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Elliott H Sohn - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Megan J Riker - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Luke A Wiley - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Todd E Scheetz - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Edwin M Stone - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Budd A Tucker - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Robert F Mullins - Stephen A Wynn Institute for Vision Research and Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: The Journal of pathology, Vol.238(3), pp.446-456
DOI: 10.1002/path.4669
PMID: 26564985
PMCID: PMC4900182
NLM abbreviation: J Pathol
ISSN: 0022-3417
eISSN: 1096-9896
Publisher: England
Grant note: T32 GM008629 / NIGMS NIH HHS EY-023187 / NEI NIH HHS R01 EY024605 / NEI NIH HHS EY-024605 / NEI NIH HHS DP2 OD007483 / NIH HHS 1-DP2-OD007483-01 / NIH HHS R01 EY023187 / NEI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979978902771

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