Fiche publication
Date publication
janvier 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Mme THIBAULT-CARPENTIER Christelle
Tous les auteurs :
Fouillade C, Baron-Menguy C, Domenga-Denier V, Thibault C, Takamiya K, Huganir R, Joutel A
Lien Pubmed
Résumé
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-J kappa 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 gamma-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-J kappa 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. Conclusion-Our data provide insight into how Notch3 signals in the brain arteries, establishing the postnatal requirement of smooth muscle RBP-J kappa in this context. Notch3-regulated transcriptome provides potential for modulating myogenic response in the cerebrovasculature. (Arterioscler Thromb Vasc Biol. 2013;33:76-86.)
Référence
Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):76-86
