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Mausmodelle zur Erforschung der Intimahyperplasie

Research in intimal hyperplasia: mouse models

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Zusammenfassung

Die Intimahyperplasie (IH) ist eines der Hauptprobleme nach Eingriffen am Gefäßsystem. Obwohl man zahlreiche pathophysiologische Vorgänge mit der IH in Verbindung bringen kann, sind die genauen molekularen Mechanismen weitestgehend unbekannt. Zur detaillierten Erforschung dieser Prozesse werden unter anderem Knock-out-Mausmodelle mit artifizieller arterieller Läsion verwendet, mit denen eine gezielte Analyse individueller Gene möglich ist. Es konnte nachgewiesen werden, dass das Ausmaß der IH zwischen verschiedenen Inzuchtstämmen variiert. Somit können heute Genloci identifiziert werden, die mit der IH korrelieren.

Als Zielgefäß für die arterielle Verletzung eignet sich in der Maus besonders die A. carotis. Dabei gibt es verschiedene Wege, die IH zu erzeugen: Endothelfreilegung durch Nylonschlinge oder Führungsdraht, Ligatur der A. carotis communis, Angioplastie mittels Ballonkatheter und Veneninterponate.

Im vorliegenden Artikel werden zwei wichtige Forschungsgebiete näher erläutert. Zunächst wird auf die Bedeutung des bioaktiven Lipids Sphingosin-1-Phosphat (S1P) eingegangen. Den Studienergebnissen nach ist S1P für die Differenzierung der glatten Muskelzellen (GM) der Media über eine Aktivierung des Typ-2-Rezeptors verantwortlich. Die auf diese Weise induzierte Expression von GM-Differenzierungsgenen scheint die Proliferation der GM zu hemmen, und somit die IH zu limitieren. Als zweites Forschungsgebiet wird die Rolle der Stammzellen im Rahmen der IH diskutiert. So wurden in den intimalen Läsionen der Mausarterie endotheliale Progenitorzellen (EPC) und aus dem Knochenmark stammende mesenchymale Stammzellen gefunden. Die Funktion dieser Zellen ist jedoch noch unklar.

Ein auf den ersten Blick irritierender Aspekt in der IH-Forschung ist die Beobachtung, dass nicht nur die Art der Verletzung, sondern auch die Topografie des Gefäßes das Ausmaß der IH beeinflusst. Zusammenfassend definieren also verschiedene Parameter die Reaktion des Gefäßes auf die Verletzung. Die Mechanismen, die zur Ausbildung der IH führen, scheinen demnach keineswegs so einheitlich zu sein, wie bisher angenommen.

Abstract

Intimal hyperplasia (IH) is one of the major problems after vascular interventions. Despite the identification of multiple processes thought to be involved, the molecular mechanisms controlling IH are still not understood. Mouse models of arterial injury are now widely used to study IH because they allow the investigation of individual genes in knock-out animals. Moreover, it has been demonstrated that the extent of IH varies among inbred strains; thus, mouse models can be used to identify genetic loci that correlate with IH.

A suitable vessel for injury experiments in mice is the carotid artery. There are different ways to induce IH in the mouse carotid: denudation of the endothelium with a catheter (nylon loop or angioplasty guide wire), complete ligation of the common carotid, dilatation by a balloon catheter, or venous grafts.

In this paper, current studies in two areas of IH research are presented. First, a novel role for the bioactive lipid sphingosine-1-phosphate (S1P) is described. The hypothesis is that S1P promotes differentiation of smooth muscle cells (SMCs) by activating the type-2 receptor for S1P. Increased expression of SMC differentiation genes is thought to restrict the proliferative potential of these cells, thereby limiting IH. Second, a role for stem cells in IH is discussed. Although functional data are largely lacking, endothelial progenitor cells as well as mesenchymal stem cells have been found in murine intimal lesions.

A potentially confounding aspect in IH research are observations indicating that the extent of IH after arterial injury depends not only on the nature of the injury but also on the vascular bed.

In conclusion, multiple parameters define the reponse to arterial injury; therefore, the mechanisms underlying IH may be much less uniform than commonly assumed.

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Authors and Affiliations

  1. Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I), Universitätsklinik Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland

    A. Larena-Avellaneda & M. Winkler

  2. Department of Pathology, University of Washington, Washington, USA

    T. Shimizu & M.A. Reidy

  3. Department of Surgery, University of Washington, Washington, USA

    G. Daum

Authors
  1. A. Larena-Avellaneda
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  2. M. Winkler
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  3. T. Shimizu
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  4. M.A. Reidy
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  5. G. Daum
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Correspondence to A. Larena-Avellaneda.

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Larena-Avellaneda, A., Winkler, M., Shimizu, T. et al. Mausmodelle zur Erforschung der Intimahyperplasie. Gefässchirurgie 14, 9–15 (2009). https://doi.org/10.1007/s00772-008-0649-x

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  • DOI: https://doi.org/10.1007/s00772-008-0649-x

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