|Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature.|
|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|
|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-01|
|Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 33 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2013 Jan|
|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|
|Languages: eng Pagination: 76-86 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
analogs & derivatives,
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
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
Vasoconstriction* / drug effects
Vasoconstrictor Agents / pharmacology
Vasodilator Agents / pharmacology
|NS36715/NS/NINDS NIH HHS; R01 NS054122/NS/NINDS NIH HHS; R01 NS054122/NS/NINDS NIH HHS|
|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|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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