Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation

Kurt A. Zimmerman, Dongqi Xing, Manuel A. Pallero, Ailing Lu, Masahito Ikawa, Leland Black, Kenneth L. Hoyt, Janusz H. Kabarowski, Marek Michalak, Joanne E. Murphy-Ullrich

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background/Aims: The endoplasmic reticulum (ER) stress protein, calreticulin (CRT), is required for the production of TGF-β-stimulated extracellular matrix (ECM) by fibroblasts. Since TGF-β regulates vascular fibroproliferative responses and collagen deposition, we investigated the effects of CRT knockdown on vascular smooth-muscle cell (VSMC) fibroproliferative responses and collagen deposition. Methods: Using a carotid artery ligation model of vascular injury, Cre-recombinase-IRES-GFP plasmid was delivered with microbubbles (MB) to CRT-floxed mice using ultrasound (US) to specifically reduce CRT expression in the carotid artery. Results: In vitro, Cre-recombinase-mediated CRT knockdown in isolated, floxed VSMCs decreased the CRT transcript and protein, and attenuated the induction of collagen I protein in response to TGF-β. TGF-β stimulation of collagen I was partly blocked by the NFAT inhibitor 11R-VIVIT. Following carotid artery ligation, CRT staining was upregulated with enhanced expression in the neointima 14-21 days after injury. Furthermore, Cre-recombinase-IRES-GFP plasmid delivered by targeted US reduced CRT expression in the neointima of CRT-floxed mice and led to a significant reduction in neointima formation and collagen deposition. The neointimal cell number was also reduced in mice, with a local, tissue-specific knockdown of CRT. Conclusions: This work establishes a novel role for CRT in mediating VSMC responses to injury through the regulation of collagen deposition and neointima formation.

Original languageEnglish (US)
Pages (from-to)306-320
Number of pages15
JournalJournal of Vascular Research
Volume52
Issue number5
DOIs
StatePublished - Apr 1 2016

Keywords

  • Calreticulin
  • Collagen
  • Neointima formation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Zimmerman, K. A., Xing, D., Pallero, M. A., Lu, A., Ikawa, M., Black, L., Hoyt, K. L., Kabarowski, J. H., Michalak, M., & Murphy-Ullrich, J. E. (2016). Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation. Journal of Vascular Research, 52(5), 306-320. https://doi.org/10.1159/000443884