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Decreased Neointimal Extracellular Matrix Formation in RAGE-Knockout Mice After Microvascular Denudation

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Abstract

Purpose

To evaluate in vivo the role of RAGE (receptor for advanced glycated end products) in the development of restenosis and neointimal proliferation in RAGE-deficient knockout (KO) mice compared with wild-type (WT) mice in an animal model.

Materials and Methods

Sixteen WT and 15 RAGE-deficient mice underwent microvascular denudation of the common femoral artery under general anaesthesia. Contralateral arteries underwent a sham operation and served as controls. Four weeks after the intervention, all animals were killed, and paraformaldehyde-fixed specimens of the femoral artery were analysed with different stains (hematoxylin and eosin and Elastica van Gieson) and several different types of immunostaining (proliferating cell nuclear antigen, α-actin, collagen, von Willebrand factor, RAGE). Luminal area, area of the neointima, and area of the media were measured in all specimens. In addition, colony-formation assays were performed, and collagen production by WT smooth muscle cells (SMCs) and RAGE-KO SMCs was determined. For statistical analysis, P < 0.05 was considered statistically significant.

Results

Four weeks after denudation, WT mice showed a 49.6% loss of luminal area compared with 14.9% loss of luminal area in RAGE-deficient mice (sham = 0% loss) (P < 0.001). The neointima was 18.2 (*1000 μm2 [n = 15) in the WT group compared with only 8.4 (*1000 μm2 [n = 16]) in the RAGE-KO group. RAGE-KO SMCs showed significantly decreased proliferation activity and production of extracellular matrix protein.

Conclusion

RAGE may be shown to play a considerable role in the formation of neointima leading to restenosis after vascular injury.

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Acknowledgments

This study was supported in part by grants from the interdisciplinary center for clinical research, University of Tübingen. This publication reflects only the authors’ views. The authors are not liable for any use that may be made of information herein.

Conflict of interest

Gerd Grözinger has no conflict of interest to declare. Jörg Schmehl has no conflict of interest to declare. Rüdiger Bantleon has no conflict of interest to declare. Rainer Kehlbach has no conflict of interest to declare. Tarun Mehra has no conflict of interest to declare. Claus D. Claussen has no conflict of interest to declare. Benjamin Wiesinger has no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Diagnostic and Interventional Radiology, University of Tübingen, Hoppe-Seylerstr 3, 72076, Tübingen, Germany

    Gerd Grözinger, Jörg Schmehl, Claus Claussen & Benjamin Wiesinger

  2. Department of Diagnostic and Interventional Radiology, University of Tübingen, Waldhörnlestraße 3, 72072, Tübingen, Germany

    Rüdiger Bantleon & Rainer Kehlbach

  3. Department of Dermatology, University of Tübingen, Liebermeisterstraße 25, 72076, Tübingen, Germany

    Tarun Mehra

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  1. Gerd Grözinger
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Correspondence to Jörg Schmehl.

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Grözinger, G., Schmehl, J., Bantleon, R. et al. Decreased Neointimal Extracellular Matrix Formation in RAGE-Knockout Mice After Microvascular Denudation. Cardiovasc Intervent Radiol 35, 1439–1447 (2012). https://doi.org/10.1007/s00270-011-0319-3

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