Notch Initiates the Endothelial-to-Mesenchymal Transition in the Atrioventricular Canal through Autocrine Activation of Soluble Guanylyl Cyclase

Alex C Y Chang, YangXin Fu, Victoria C. Garside, Kyle Niessen, Linda Chang, Megan Fuller, Audi Setiadi, Justin Smrz, Alastair Kyle, Andrew Minchinton, Marco Marra, Pamela A. Hoodless, Aly Karsan

Research output: Contribution to journalArticleResearchpeer-review

100 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)288-300
Number of pages13
JournalDevelopmental Cell
Volume21
Issue number2
DOIs
Publication statusPublished - 16 Aug 2011
Externally publishedYes

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