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PMID:16452172

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Citation

Nozaki, M, Raisler, BJ, Sakurai, E, Sarma, JV, Barnum, SR, Lambris, JD, Chen, Y, Zhang, K, Ambati, BK, Baffi, JZ and Ambati, J (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl. Acad. Sci. U.S.A. 103:2328-33

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.

Links

PubMed PMC1413680 Online version:10.1073/pnas.0408835103

Keywords

Aged, 80 and over; Animals; Choroidal Neovascularization/genetics; Choroidal Neovascularization/metabolism; Complement C3a/analysis; Complement C3a/genetics; Complement C3a/metabolism; Complement C5a/analysis; Complement C5a/genetics; Complement C5a/metabolism; Female; Humans; Macular Degeneration/genetics; Macular Degeneration/metabolism; Male; Mice; Mice, Mutant Strains; Retinal Drusen/genetics; Retinal Drusen/immunology; Retinal Drusen/metabolism; Vascular Endothelial Growth Factor A/genetics; Vascular Endothelial Growth Factor A/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:C3AR

involved_in

GO:0010759: positive regulation of macrophage chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C3AR

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C3AR

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C3AR

involved_in

GO:0090023: positive regulation of neutrophil chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CO3

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CO5

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CO5

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C5AR1

involved_in

GO:0010759: positive regulation of macrophage chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C5AR1

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C5AR1

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:C5AR1

involved_in

GO:0090023: positive regulation of neutrophil chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CO3

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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