C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice.
BACKGROUND
Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody.


RESULTS
Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-alpha, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration.


CONCLUSIONS
One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. However, treatment for 3 weeks failed to reduce but rather stabilized plaques, likely by reducing vascular plasminogen activator inhibitor-1 and increasing vascular smooth muscle cell migration.
Shagdarsuren
Erdenechimeg
E
Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
Bidzhekov
Kiril
K
Mause
Sebastian F
SF
Simsekyilmaz
Sakine
S
Polakowski
Thomas
T
Hawlisch
Heiko
H
Gessner
J Engelbert
JE
Zernecke
Alma
A
Weber
Christian
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007962:Leukocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D058258:Serpin E2; D015843:Serpins / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D009842:Oligopeptides; D044087:Receptor, Anaphylatoxin C5a; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D019010:Vascular Cell Adhesion Molecule-1; D015936:Complement C5a