Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis

MacGrogan, Donal; D’Amato, Gaetano; Travisano, Stanislao Igor; Martínez‐Poveda, Beatriz; Luxán, Guillermo; Monte‐Nieto, Gonzalo del; Papoutsi, Tania; Sbroggiò, Mauro; Bou, Vanesa; Arco, Pablo Gómez-del; Gómez, Manuel J.; Zhou, Bin; Redondo, Juan Miguel; Jiménez-Borreguero, Luis Jesús; Pompa, José Luis de la

doi:10.1161/circresaha.115.308077

Cited by 108 publications

(184 citation statements)

References 64 publications

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“…MFNG gene was also significantly downregulated in BAV-D compared to TAV-D ( P < 0.00001, Supplementary Table 9). This was in line with the data published in mice25, supporting the regulatory role of MIB1 and MFNF for NOTCH pathway in BAV.…”

Section: Resultssupporting

confidence: 92%

“…Fine tuning of NOTCH ligand-receptor interaction, either by ligand endocytosis activated by E3 ubiquitin ligase Mind Bomb ( MIB1) or by post translational modification of receptor via glycosyltransferase Manic Fringe ( MFNG ) in endocardium was reported to be required for the proper EndMT of cardiac cushion and formation of aortic valves in mice25. Using IHC, we showed a significantly higher expression of NOTCH3 and NOTCH1 intracellular domain (ICD), the ligands JAG1, JAG2, and DLL4 and a higher tendency for NOTCH4 expression ( P = 0.0571) in intima-media of BAV-ND compared to TAV-ND (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Maleki

Kjellqvist

Paloschi

et al. 2016

Sci Rep

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Individuals with a bicuspid aortic valve (BAV) are at significantly higher risk of developing aortic complications than individuals with tricuspid aortic valves (TAV) and defective signaling during the embryonic development and/or life time exposure to abnormal hemodynamic have been proposed as underlying factors. However, an explanation for the molecular mechanisms of aortopathy in BAV has not yet been provided. We combined proteomics, RNA analyses, immunohistochemistry, and electron microscopy to identify molecular differences in samples of non-dilated ascending aortas from BAV (N = 62) and TAV (N = 54) patients. Proteomic analysis was also performed for dilated aortas (N = 6 BAV and N = 5 TAV) to gain further insight into the aortopathy of BAV. Our results collectively showed the molecular signature of an endothelial/epithelial-mesenchymal (EndMT/EMT) transition-like process, associated with instability of intimal cell junctions and activation of RHOA pathway in the intima and media layers of ascending aorta in BAV patients. We propose that an improper regulation of EndMT/EMT during the spatiotemporally related embryogenesis of semilunar valves and ascending aorta in BAV individuals may result in aortic immaturity and instability prior to dilation. Exasperation of EndMT/EMT state in post embryonic life and/or exposure to non-physiological hemodynamic could lead to the aneurysm of ascending aorta in BAV individuals.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Maleki

Kjellqvist

Paloschi

et al. 2016

Sci Rep

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“…Although it is still unclear how to link discrete JAG1 mutations, which have variable effects on JAG1 trafficking and activity, to the range of cardiac defects observed in individuals with Alagille syndrome (Bauer et al, 2010), it has been shown that the development of several compartments of the heart is dependent on the balanced activities of Jag1 and Notch2. Ablation of Jag1 expression in the endocardium leads to outflow tract (OFT) defects, aortic valve hyperplasticity, tetralogy of Fallot and valve calcification, recapitulating the spectrum of cardiac pathologies often present in Alagille syndrome MacGrogan et al, 2016). These phenotypes are, at least partially, linked to cardiac neural crest (CNC) cells, a highly migratory cell population that originates from the neural plate border .…”

Section: Notch2 and Jag1 Function In Heart Developmentmentioning

confidence: 99%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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“…Deletion of endothelial-derived Jag1 in a subset of endothelial cells that do not undergo EMT leads to thickened arterial valves, BAV, and VSD that was shown to be mediated by endothelial-Notch1. Transcriptome analysis revealed increased BMP signaling and mesenchymal cell proliferation, and also led to the identification of a new Notch effector, Heparin binding epidermal growth factor (EGF) like growth factor, required to suppress mesenchymal cell proliferation and potentially play a role in embryonic valve hypertrophy [29]. …”

Section: Molecular Pathways For Aortic Valve Developmentmentioning

confidence: 99%

Genetic basis of aortic valvular disease

Koenig

Lincoln

Garg

2017

Current Opinion in Cardiology

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Purpose of Review Aortic valve disease is relatively common and encompasses both congenital and acquired forms. Bicuspid aortic valve (BAV) is the most common type of cardiac malformation and predisposes to the development of calcific aortic valve disease (CAVD). Since the description of the link between NOTCH1 and BAV and CAVD approximately a decade ago, there have been significant advances in the genetic and molecular understanding of these diseases. Recent findings Recent work has defined the congenital cardiac phenotypes linked to mutations in NOTCH1 and in addition, novel etiologic genes for BAV have been discovered using new genetic technologies in humans. Furthermore, several mouse models of BAV have been described defining the role of endothelial Notch1 in aortic valve morphogenesis while others have implicated new genes. These murine models along with other cell-based studies have led to molecular insights in the pathogenesis of CAVD. Summary These findings provide important insights into the molecular and genetic basis of aortic valve malformations, including BAV, specifically highlighting the etiologic role of endothelial cells. In addition, numerous investigations in the mechanisms of CAVD demonstrate the importance of developmental origins and signaling pathways as well as communication between valve endothelial cells and the underlying interstitial cells in valve disease onset and progression.

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Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis

Cited by 108 publications

References 64 publications

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

The developmental biology of genetic Notch disorders

Genetic basis of aortic valvular disease

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