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Blockade of Angio-Associated Migratory Cell Protein Inhibits Smooth Muscle Cell Migration and Neointima Formation in Accelerated Atherosclerosis

Felix Vogt, MD^_*, Alma Zernecke, MD, Marie Beckner, PhD, Nicole Krott, MSc^_*,, Anja-Katrin Bosserhoff, PhD^||, Rainer Hoffmann, MD^_*, Marc A.M.J. Zandvoort, PhD^#, Thomas Jahnke, MD^¶, Malte Kelm, MD^_*, Christian Weber, MD and Rüdiger Blindt, MD^_*,_*

^_* Department of Cardiology, RWTH Aachen University, Aachen, Germany
Interdisciplinary Center of Clinical Research (IZKF) "BIOMAT" within the faculty of Medicine, RWTH Aachen University, Aachen, Germany
Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
Department of Pathology, Pittsburgh University Medical Center, Pittsburgh, Pennsylvania
^|| Institute of Pathology, University of Regensburg, Regensburg, Germany
^¶ Department of Diagnostic Radiology, University Clinics Schleswig-Holstein, Campus Kiel, Germany
^# Department of Biophysics, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands.

Manuscript received October 1, 2007; revised manuscript received February 4, 2008, accepted March 4, 2008.

^_* Reprint requests and correspondence: Dr. Rüdiger Blindt, Department of Cardiology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. (Email: rblindt{at}ukaachen.de).

Objectives: 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.

Key Words: atherosclerosis • migration • neointima formation • restenosis • smooth muscle cells

Abbreviations and Acronyms   AAMP = angio-associated migratory cell protein   anti-rAAMP-ab = recombinant angio-associated migratory cell protein–antibody   apoE–/– = apolipoprotein E knockout   FITC = fluorescein isothiocyanate   GFP = green fluorescent protein   hSMC = human smooth muscle cell   NI = neointima   rSMC = rat smooth muscle cell   siRNA = small interfering ribonucleic acid   SMA = smooth muscle actin

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