Document Detail

Smooth muscle Notch1 mediates neointimal formation after vascular injury.
MedLine Citation:
PMID:  19433762     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Notch1 regulates binary cell fate determination and is critical for angiogenesis and cardiovascular development. However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury.
METHODS AND RESULTS: We performed carotid artery ligation in wild-type, control (SMC-specific Cre recombinase transgenic [smCre-Tg]), general Notch1 heterozygous deficient (N1+/-), SMC-specific Notch1 heterozygous deficient (smN1+/-), and general Notch3 homozygous deficient (N3-/-) mice. Compared with wild-type or control mice, N1+/- and smN1+/- mice showed a 70% decrease in neointimal formation after carotid artery ligation. However, neointimal formation was similar between wild-type and N3-/- mice. Indeed, SMCs derived from explanted aortas of either N1(+/-)- or smN1+/- mice showed decreased chemotaxis and proliferation and increased apoptosis compared with control or N3-/- mice. This correlated with decreased staining of proliferating cell nuclear antigen-positive cells and increased staining of cleaved caspase-3 in the intima of N1(+/-)- or smN1+/- mice. In SMCs derived from CHF1/Hey2-/- mice, activation of Notch signaling did not lead to increased SMC proliferation or migration.
CONCLUSIONS: These findings indicate that Notch1, rather than Notch3, mediates SMC proliferation and neointimal formation after vascular injury through CHF1/Hey2 and suggest that therapies that target Notch1/CHF1/Hey2 in SMCs may be beneficial in preventing vascular proliferative diseases.
Yuxin Li; Kyosuke Takeshita; Ping-Yen Liu; Minoru Satoh; Naotsugu Oyama; Yasushi Mukai; Michael T Chin; Luke Krebs; Michael I Kotlikoff; Freddy Radtke; Thomas Gridley; James K Liao
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-11
Journal Detail:
Title:  Circulation     Volume:  119     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-27     Completed Date:  2009-06-24     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2686-92     Citation Subset:  AIM; IM    
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MeSH Terms
Aorta / cytology
Basic Helix-Loop-Helix Transcription Factors / deficiency,  physiology*
Blood Vessels / injuries*
Carotid Arteries
Cell Proliferation
Mice, Knockout
Muscle, Smooth, Vascular / physiology*
Myocytes, Smooth Muscle / physiology
Receptor, Notch1 / deficiency,  physiology*
Receptors, Notch / deficiency
Repressor Proteins / physiology*
Tunica Intima / growth & development*
Grant Support
DK065992/DK/NIDDK NIH HHS; HL052233/HL/NHLBI NIH HHS; HL080187/HL/NHLBI NIH HHS; NS036437/NS/NINDS NIH HHS; P50 NS010828/NS/NINDS NIH HHS; P50 NS010828-310036/NS/NINDS NIH HHS; P50 NS010828-320036/NS/NINDS NIH HHS; R01 DK062729/DK/NIDDK NIH HHS; R01 DK062729-04/DK/NIDDK NIH HHS; R01 DK062729-05/DK/NIDDK NIH HHS; R01 HL052233/HL/NHLBI NIH HHS; R01 HL052233-11/HL/NHLBI NIH HHS; R01 HL052233-12/HL/NHLBI NIH HHS; R01 HL052233-13/HL/NHLBI NIH HHS; R01 HL070274/HL/NHLBI NIH HHS; R01 HL070274-03/HL/NHLBI NIH HHS; R01 HL070274-04/HL/NHLBI NIH HHS; R01 HL070274-05/HL/NHLBI NIH HHS; R01 HL080187/HL/NHLBI NIH HHS; R01 HL080187-02/HL/NHLBI NIH HHS; R01 HL080187-03/HL/NHLBI NIH HHS; R01 HL080187-04/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Hey2 protein, mouse; 0/Notch3 protein, mouse; 0/Receptor, Notch1; 0/Receptors, Notch; 0/Repressor Proteins

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