Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice

Lena S. Kiene, Susanne Homann, Tatsiana Suvorava, Berit Rabausch, Julia Müller, Georg Kojda, Inga Kretschmer, Sören Twarock, Guang Dai, René Deenen, Sonja Hartwig, Stefan Lehr, Karl Köhrer, Rashmin C. Savani, Maria Grandoch, Jens W. Fischer

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Objective-Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. Approach and Results-Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ligation, and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both, the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings, immunoblotting of endothelial nitric oxide synthase, and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted toward a mitigated differential regulation of various signaling pathways in Has3-deficient mice in response to ligation that were related to vascular smooth muscle cell (VSMC) migration, including focal adhesions, integrins, mitogen-activated protein kinase, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in VSMC supported the migratory phenotype of VSMC in response to platelet-derived growth factor BB in vitro. Accordingly, knockdown of HAS3 reduced the migratory response to platelet-derived growth factor BB and in addition decreased the expression of PDGF-B mRNA. Conclusions-HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases platelet-derived growth factor BB-mediated migration, and in turn enhances neointimal hyperplasia in vivo.

Original languageEnglish (US)
Pages (from-to)e9-e16
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • carotid arteries
  • extracellular matrix
  • hyaluronan
  • neointima
  • smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Kiene, L. S., Homann, S., Suvorava, T., Rabausch, B., Müller, J., Kojda, G., Kretschmer, I., Twarock, S., Dai, G., Deenen, R., Hartwig, S., Lehr, S., Köhrer, K., Savani, R. C., Grandoch, M., & Fischer, J. W. (2016). Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice. Arteriosclerosis, thrombosis, and vascular biology, 36(2), e9-e16. https://doi.org/10.1161/ATVBAHA.115.306607