Document Detail

Endothelial FGF receptor signaling accelerates atherosclerosis.
MedLine Citation:
PMID:  20952669     Owner:  NLM     Status:  MEDLINE    
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.
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
Related Documents :
16259589 - Improved microvascular network in vitro by human blood outgrowth endothelial cells rela...
20187999 - The soyabean isoflavone genistein modulates endothelial cell behaviour.
19507189 - Fibrinogen induces alterations of endothelial cell tight junction proteins.
18551989 - Dual vascular effects of leptin via endothelium: hypothesis and perspective.
19143939 - Review article: leukocyte-endothelial dysregulation in systemic small vessel vasculitis.
20932129 - The effect of laser preexposure on seeding endothelial cells to a biomaterial surface.
22722639 - The role of vascular endothelial growth factor in ossification.
7522209 - Expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 i...
12851209 - Pecam-directed delivery of catalase to endothelium protects against pulmonary vascular ...
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    
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Analysis of Variance
Aorta / metabolism,  physiopathology
Atherosclerosis / metabolism*,  physiopathology
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Endothelial Cells / metabolism*
Endothelium, Vascular / metabolism*,  physiopathology
Mice, Transgenic
Receptors, Fibroblast Growth Factor / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / physiology*
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Receptors, Fibroblast Growth Factor
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

Previous Document:  Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion.
Next Document:  Assessment of flow-mediated dilation in humans: a methodological and physiological guideline.