NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease

Abstract

NOTCH intercellular signaling mediates the communications between adjacent cells involved in multiple biological processes essential for tissue morphogenesis and homeostasis. The NOTCH1 mutations are the first identified human genetic variants that cause congenital bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). Genetic variants affecting other genes in the NOTCH signaling pathway may also contribute to the development of BAV and the pathogenesis of CAVD. While CAVD occurs commonly in the elderly population with tri-leaflet aortic valve, patients with BAV have a high risk of developing CAVD at a young age. This observation indicates an important role of NOTCH signaling in the postnatal homeostasis of the aortic valve, in addition to its prenatal functions during aortic valve development. Over the last decade, animal studies, especially with the mouse models, have revealed detailed information in the developmental etiology of congenital aortic valve defects. In this review, we will discuss the molecular and cellular aspects of aortic valve development and examine the embryonic pathogenesis of BAV. We will focus our discussions on the NOTCH signaling during the endocardial-to-mesenchymal transformation (EMT) and the post-EMT remodeling of the aortic valve. We will further examine the involvement of the NOTCH mutations in the postnatal development of CAVD. We will emphasize the deleterious impact of the embryonic valve defects on the homeostatic mechanisms of the adult aortic valve for the purpose of identifying the potential therapeutic targets for disease intervention.

Angiopoietin-like 2 is essential to aortic valve development in mice

“…Our data demonstrate that the expression of the Notch signalling pathway is reduced in AoV leaflets of Angptl2-KD mice both at embryonic and adult stages, of both sexes. The key role of Notch signalling in valve development and homeostasis has been extensively studied 63 and, accordingly, Notch deficiency is involved in congenital heart valve diseases such as BAV or acquired disorders such as calcific AoV disease [48][49][50][51] . Little is known about the potential link between ANGPTL2 and Notch signalling, but our data strongly suggest that ANGPTL2 regulates Notch-dependent remodelling processes: i) ANGPTL2 and NOTCH1 are both co-expressed in endothelial cells during AoV remodelling at E14.5 in the border of the leaflet, ii) there is a decrease of Notch signalling with a deregulation of proliferation, senescence and apoptosis in the AoV leaflets of Angptl2-KD mice and iii) the decrease in Notch1, Hey1 and Hey2 mRNA expressions were highly correlated to the decrease of AoV area and increase of AoV leaflet thickness, i.e., to the severity of AVS observed in Angptl2-KD mice.…”

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

“…Both pathways are known to be involved in heart formation and development. Furthermore, genetic variations in NOTCH and VEGF genes have been found in patients with CHD [ 42 , 43 ]. In the present study, we sought to identify genetic variants in ROBO and SLIT genes in patients with different CHD.…”

Dysregulated insulin secretion is associated with pancreatic β‐cell hyperplasia and direct acinar‐β‐cell trans‐differentiation in partially eNOS ‐deficient mice

“…There are actually several lines of evidence linking Notch‐1 signaling with the eNOS‐NO pathway. Firstly, it has been shown that in aortic valve interstitial cells (AVICs), endothelial cell‐derived NO enhances the nuclear localization of NICD and regulates the expression of Notch‐ 1 target genes, thereby preventing aortic valve calcification (Bosse et al, 2013; Majumdar et al, 2021; Wang et al, 2021). Conversely, the reduced NO production, as occurs in endothelial cell dysfunction or in eNOS knockout mice, can in turn inhibit Notch‐1 signaling in AVICs and favor aortic valve calcification (Bosse et al, 2013; Garg, 2016).…”