Document Detail


Notch3 is critical for proper angiogenesis and mural cell investment.
MedLine Citation:
PMID:  20689064     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: The heterotypic interactions of endothelial cells and mural cells (smooth muscle cells or pericytes) are crucial for assembly, maturation, and subsequent function of blood vessels. Yet, the molecular mechanisms underlying their association have not been fully defined.
OBJECTIVE: Our previous in vitro studies indicated that Notch3, which is expressed in mural cells, mediates these cell-cell interactions. To assess the significance of Notch3 on blood vessel formation in vivo, we investigated its role in retinal angiogenesis.
METHODS AND RESULTS: We show that Notch3-deficient mice exhibit reduced retinal vascularization, with diminished sprouting and vascular branching. Moreover, Notch3 deletion impairs mural cell investment, resulting in progressive loss of vessel coverage. In an oxygen-induced retinopathy model, we demonstrate that Notch3 is induced in hypoxia and interestingly, pathological neovascularization is decreased in retinas of Notch3-null mice. Analysis of oxygen-induced retinopathy mediators revealed that angiopoietin-2 expression is significantly reduced in the absence of Notch3. Furthermore, in vitro experiments showed that Notch3 is sufficient for angiopoietin-2 induction, and this expression is additionally enhanced in the presence of hypoxia-inducible factor 1α.
CONCLUSIONS: These results provide compelling evidence that Notch3 is important for the investment of mural cells and is a critical regulator of developmental and pathological blood vessel formation.
Authors:
Hua Liu; Wenbo Zhang; Simone Kennard; Ruth B Caldwell; Brenda Lilly
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-05
Journal Detail:
Title:  Circulation research     Volume:  107     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-01     Completed Date:  2010-10-22     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  860-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Angiopoietin-2 / genetics
Animals
Anoxia / physiopathology
Aorta / cytology,  physiology
Cell Communication / physiology
Cells, Cultured
Endothelial Cells / cytology,  physiology
Gene Expression Regulation / physiology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Mice
Mice, Mutant Strains
Muscle, Smooth, Vascular / cytology,  physiology*
Neovascularization, Pathologic / physiopathology*
Neovascularization, Physiologic / physiology*
Oxygen / toxicity
Pericytes / cytology,  physiology*
Receptors, Notch / genetics*,  metabolism
Retinal Vessels / cytology,  physiology
Grant Support
ID/Acronym/Agency:
R01 HL076428/HL/NHLBI NIH HHS; R01 HL076428/HL/NHLBI NIH HHS; R01 HL076428-01A2/HL/NHLBI NIH HHS; R01 HL076428-02/HL/NHLBI NIH HHS; R01 HL076428-03/HL/NHLBI NIH HHS; R01 HL076428-04/HL/NHLBI NIH HHS; R01 HL076428-05/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Angiopoietin-2; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/NOTCH3 protein, human; 0/Notch3 protein, mouse; 0/Receptors, Notch; S88TT14065/Oxygen
Comments/Corrections

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


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