1. Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase.
- Author
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Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, and Karsan A
- Subjects
- Animals, Cells, Cultured, Chromatin Immunoprecipitation methods, Female, Gene Expression Profiling methods, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type III deficiency, Oligonucleotide Array Sequence Analysis methods, RNA Interference physiology, Signal Transduction, Soluble Guanylyl Cyclase, Endocardial Cushions cytology, Endothelium physiology, Guanylate Cyclase metabolism, Mesoderm physiology, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Notch metabolism
- Abstract
The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC)., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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