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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, RESULTS. Meshes: Alanine, Amyloid Precursor Protein Secretases, Animals, Azepines, Carrier Proteins, Cerebral Arteries, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Kv1.5 Potassium Channel, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Nerve Tissue Proteins, Receptor, Notch3, Receptors, Notch, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Vasoconstriction, Vasoconstrictor Agents, Vasodilation, Vasodilator Agents.
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Does transcriptome analysis for Notch3 target genes identify Grip2 as a novel regulator of myogenic response in the cerebrovasculature? Context: 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. 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.
assistant
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. Final Decision: yes