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Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation.


ABSTRACT: The endoplasmic reticulum (ER) stress protein, calreticulin (CRT), is required for the production of TGF-?-stimulated extracellular matrix (ECM) by fibroblasts. Since TGF-? 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.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.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-?. TGF-? 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.This work establishes a novel role for CRT in mediating VSMC responses to injury through the regulation of collagen deposition and neointima formation.

SUBMITTER: Zimmerman KA 

PROVIDER: S-EPMC4816666 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation.

Zimmerman Kurt A KA   Xing Dongqi D   Pallero Manuel A MA   Lu Ailing A   Ikawa Masahito M   Black Leland L   Hoyt Kenneth L KL   Kabarowski Janusz H JH   Michalak Marek M   Murphy-Ullrich Joanne E JE  

Journal of vascular research 20150101 5


<h4>Background/aims</h4>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.<h4>Methods</h4>Using a carotid artery ligation model of vascular injury, Cre-recombinase-IRES  ...[more]

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