Blockade of angio-associated migratory cell protein inhibits smooth muscle cell migration and neointima formation in accelerated atherosclerosis.
OBJECTIVE
The aim of this study was to elucidate the role of angio-associated migratory cell protein (AAMP) for the migration of vascular smooth muscle cells (SMCs) and for the development of neointimal hyperplasia after vascular injury.


BACKGROUND
Although AAMP has been shown to participate in angiogenesis and cancerogenesis and is predominantly expressed in cells with a migratory phenotype, involvement of AAMP during neointima (NI) formation after arterial injury has not been analyzed previously.


METHODS
The AAMP content in SMCs was examined using 2-photon laser-scanning microscopy and subcellular fractioning. Migratory potential of SMCs transiently transfected with AAMP expression vectors, transfected with small interfering ribonucleic acid (siRNA), or treated with antirecombinant angio-associated migratory cell protein-antibody (anti-rAAMP-ab) was examined using transwell migration chamber assays. Expression of AAMP was determined in the atherogenic apolipoprotein E knockout (apoE(-/-)) mouse model and in the porcine coronary restenosis model by immunohistochemistry and by Western blot. ApoE(-/-) mice were treated intraperitoneally with anti-rAAMP-ab, and wire-injured carotid arteries were examined.


RESULTS
Angio-associated migratory cell protein is localized in the membrane of SMCs, and its expression is enhanced in NI-derived SMCs. The AAMP overexpression increases, while both treatment with anti-rAAMP-ab and transfection with siRNA decreases SMC migration. Knockdown of AAMP decreases RhoA activity in the membrane fraction of SMCs. The AAMP expression by SMCs is enhanced in both animal models. Anti-rAAMP-ab reduces neointimal SMC density at 1 week and NI formation at 4 weeks in apoE(-/-) mice without affecting proliferation of SMCs.


CONCLUSIONS
These data reveal an important functional role of AAMP in the migration of SMCs, identifying AAMP as a potential target to limit lesion formation after injury.
Vogt
Felix
F
Department of Cardiology, RWTH Aachen University, Aachen, Germany.
Zernecke
Alma
A
Beckner
Marie
M
Krott
Nicole
N
Bosserhoff
Anja-Katrin
AK
Hoffmann
Rainer
R
Zandvoort
Marc A M J
MA
Jahnke
Thomas
T
Kelm
Malte
M
Weber
Christian
C
Blindt
Rüdiger
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000209:etiology / Q000503:physiopathology*; D023903:Coronary Restenosis / Q000503:physiopathology; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000098:blood supply* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009389:Neovascularization, Pathologic; D011817:Rabbits; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D013552:Swine; D017539:Tunica Intima / Q000503:physiopathology*
C093492:AAMP protein, human; D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D002352:Carrier Proteins; D011947:Receptors, Antigen, B-Cell