| Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature. | |
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MedLine Citation:
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PMID: 23117660 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Charles Fouillade; Céline Baron-Menguy; Valérie Domenga-Denier; Christelle Thibault; Kogo Takamiya; Richard Huganir; Anne Joutel |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-01 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 33 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2012-12-17 Completed Date: 2013-02-12 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 76-86 Citation Subset: IM |
Affiliation:
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INSERM, U740, Paris, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alanine
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analogs & derivatives,
pharmacology Amyloid Precursor Protein Secretases / antagonists & inhibitors, metabolism Animals 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 Male Mice 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 Vasodilation Vasodilator Agents / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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NS36715/NS/NINDS NIH HHS; R01 NS054122/NS/NINDS NIH HHS; R01 NS054122/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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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; 56-41-7/Alanine; EC 3.4.-/Amyloid Precursor Protein Secretases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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