Document Detail


Endothelial FGF receptor signaling accelerates atherosclerosis.
MedLine Citation:
PMID:  20952669     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Members of the fibroblast growth factor (FGF) family have been clinically applied to the treatment of ischemic diseases because of their strong angiogenic actions. Although tissue ischemia is predominantly caused by atherosclerosis, the roles of endothelial FGF receptors (FGF-Rs) in atherosclerosis remain obscure. We generated endothelial cell (EC)-targeted constitutively active FGF-R2-overexpressing mice, using the Tie2 promoter (Tie2-FGF-R2-Tg), and crossed them with apolipoprotein E (ApoE)-deficient mice (ApoE-KO) to generate Tie2-FGF-R2-Tg/ApoE-deficient mice (Tie2-FGF-R2-Tg/ApoE-KO). After being fed a Western diet for 8 wk, the Tie2-FGF-R2-Tg/ApoE-KO demonstrated 2.0-fold greater atherosclerotic lesion area on the luminal surfaces of the aortas than the ApoE-KO (P < 0.01). The level of p21(Cip1) protein, a cell cycle inhibitor, in the FGF-R2-overexpressing EC was 2.5-fold greater than that in the wild-type (WT) EC at the baseline (P < 0.01). FGF-R2 overexpression in the EC resulted in increased expression of VCAM-1 and ICAM-1, acceleration of apoptosis, and decreased proliferative activity, all of which were normalized by small interfering RNA (siRNA)-mediated knockdown of p21(Cip1) (75% reduction in protein level, P < 0.01). Furthermore, the expression of PDGF-B and Egr-1, a PDGF/p21(Cip1)-inducible transcription factor, in the aortic endothelium of Tie2-FGF-R2-Tg/ApoE-KO was significantly greater than that in ApoE-KO. The proliferation of vascular smooth muscle cells in the aortic media of Tie2-FGF-R2-Tg/ApoE-KO was 2.0-fold higher than that in ApoE-KO (P < 0.01). Thus our study reveals that endothelial FGF-R2 signaling aggravates atherosclerosis by promoting p21(Cip1)-mediated EC dysfunction and cautions against the use of FGF for therapeutic angiogenesis in the setting of atherosclerosis.
Authors:
Jishan Che; Mitsuhiko Okigaki; Tomosaburo Takahashi; Asako Katsume; Yasushi Adachi; Shinichiro Yamaguchi; Shinsaku Matsunaga; Mitsuo Takeda; Akihiro Matsui; Eigo Kishita; Koji Ikeda; Hiroyuki Yamada; Hiroaki Matsubara
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Publication Detail:
Type:  Journal Article     Date:  2010-10-15
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  300     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-04     Completed Date:  2011-01-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H154-61     Citation Subset:  IM    
Affiliation:
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Aorta / metabolism,  physiopathology
Apoptosis
Atherosclerosis / metabolism*,  physiopathology
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Diet
Endothelial Cells / metabolism*
Endothelium, Vascular / metabolism*,  physiopathology
Immunohistochemistry
Male
Mice
Mice, Transgenic
Receptors, Fibroblast Growth Factor / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / physiology*
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Receptors, Fibroblast Growth Factor
Comments/Corrections
Comment In:
Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H27-8   [PMID:  21057042 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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