Document Detail

Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature.
MedLine Citation:
PMID:  23117660     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Notch3 is critically important for the structure and myogenic response of distal arteries, particularly of cerebral arteries. However, signaling pathways acting downstream of Notch3 remain largely unknown.
METHODS AND RESULTS: Transcriptome analysis using tail arteries of Notch3-null mice identified a core set of 17 novel Notch3-regulated genes confirmed in tail or brain arteries. Postnatal deletion of RBP-Jκ in smooth muscle cells recapitulated the structural, functional, and molecular defects of brain arteries induced by Notch3 deficiency. Transient in vivo blockade of the Notch pathway with γ-secretase inhibitors uncovered, in addition to Notch3, 6 immediate responders, including the voltage-gated potassium channel Kv1.5, which opposes to myogenic constriction of brain arteries, and the glutamate receptor-interacting protein 2 (Grip2) with no previously established role in the cerebrovasculature. We identified a vascular smooth muscle cell isoform of Grip2. We showed that Notch3-RBP-Jκ specifically regulates this isoform. Finally, we found that cerebral arteries of Grip2 mutant mice, which express an N-terminally truncated Grip2 protein, exhibited selective attenuation of pressure-induced contraction.
CONCLUSIONS: Our data provide insight into how Notch3 signals in the brain arteries, establishing the postnatal requirement of smooth muscle RBP-Jκ in this context. Notch3-regulated transcriptome provides potential for modulating myogenic response in the cerebrovasculature.
Charles Fouillade; Céline Baron-Menguy; Valérie Domenga-Denier; Christelle Thibault; Kogo Takamiya; Richard Huganir; Anne Joutel
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-01
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  33     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-02-12     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  76-86     Citation Subset:  IM    
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MeSH Terms
Alanine / analogs & derivatives,  pharmacology
Amyloid Precursor Protein Secretases / antagonists & inhibitors,  metabolism
Azepines / pharmacology
Carrier Proteins / genetics,  metabolism*
Cerebral Arteries / metabolism
Enzyme Inhibitors / pharmacology
Gene Expression Profiling
Gene Expression Regulation
Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics,  metabolism
Kv1.5 Potassium Channel / genetics,  metabolism
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular / drug effects,  growth & development,  metabolism*
Myocytes, Smooth Muscle / drug effects,  metabolism*
Nerve Tissue Proteins / deficiency,  genetics,  metabolism*
Receptors, Notch / deficiency,  genetics,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Vasoconstriction* / drug effects
Vasoconstrictor Agents / pharmacology
Vasodilator Agents / pharmacology
Grant Support
Reg. No./Substance:
0/Azepines; 0/Carrier Proteins; 0/Enzyme Inhibitors; 0/Grip2 protein, mouse; 0/Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0/Kcna5 protein, mouse; 0/Kv1.5 Potassium Channel; 0/N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; 0/Nerve Tissue Proteins; 0/Notch3 protein, mouse; 0/Rbpj protein, mouse; 0/Receptors, Notch; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; EC 3.4.-/Amyloid Precursor Protein Secretases; OF5P57N2ZX/Alanine

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