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Review
. 2014 Apr;34(4):737-41.
doi: 10.1161/ATVBAHA.113.302071.

Conserved transcriptional regulatory mechanisms in aortic valve development and disease

Elaine E Wirrig  1 , Katherine E Yutzey
Affiliations
Review

Conserved transcriptional regulatory mechanisms in aortic valve development and disease

Elaine E Wirrig et al. Arterioscler Thromb Vasc Biol. 2014 Apr.

Abstract

There is increasing evidence for activation of developmental transcriptional regulatory pathways in heart valve disease. Here, we review molecular regulatory mechanisms involved in heart valve progenitor development, leaflet morphogenesis, and extracellular matrix organization that also are active in diseased aortic valves. These include regulators of endothelial-to-mesenchymal transitions, such as the Notch pathway effector RBPJ, and the valve progenitor markers Twist1, Msx1/2, and Sox9. Little is known of the potential reparative or pathological functions of these developmental mechanisms in adult aortic valves, but it is tempting to speculate that valve progenitor cells could contribute to repair in the context of disease. Likewise, loss of either RBPJ or Sox9 leads to aortic valve calcification in mice, supporting a potential therapeutic role in prevention of disease. During aortic valve calcification, transcriptional regulators of osteogenic development are activated in addition to valve progenitor regulatory programs. Specifically, the transcription factor Runx2 and its downstream target genes are induced in calcified valves. Runx2 and osteogenic genes also are induced with vascular calcification, but activation of valve progenitor markers and the cellular context of expression are likely to be different for valve and vascular calcification. Additional research is necessary to determine whether developmental mechanisms contribute to valve repair or whether these pathways can be harnessed for new treatments of heart valve disease.

Keywords: aortic valve stenosis; bicuspid aortic valve; extracellular matrix; fetal heart; transcription factors.

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Figures

Figure 1
Figure 1. Transcription factors active in aortic valve development and disease
A. Endocardial cushions (purple) form in the cardiac outflow tract and atrioventricular canal. Valve progenitor cells are generated by an endothelial-to-mesenchymal transition (EMT) and express indicated transcription factors. B. Endocardial cushions elongate to form valve primordia of individual valve leaflets. Extracellular matrix (ECM) remodeling and morphogenesis of the valve leaflets is dependent on Nfatc1 and Gata5. C. The ECM of the semilunar valve primordia stratifies into fibrosa, spongiosa, and ventricularis layers associated with Sox9 and Scx expression. D. Calcific aortic valve disease is characterized by expression of transcription factors involved in valve development and osteogenesis. Please see text for details and citations.
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