Transcriptional regulation of heart valve development and disease

Abstract

Aortic valve disease is estimated to affect 2% of the United States population. There is increasing evidence that aortic valve disease has a basis in development, as congenital valve malformations are prevalent in patients undergoing valve replacement surgery. In fact, a number of genetic mutations have been linked to valve malformations and disease. In the initial stages of aortic valve pathogenesis, the valvular interstitial cells become activated, undergo cell proliferation, and participate in extracellular matrix remodeling. Many of these cell properties are shared with mesenchymal progenitor cells of the normally developing valves and bones. Historically, valve calcification was thought to be a passive process reflecting end-stage disease. However, recent evidence describes the increased expression of transcription factors in diseased AoV that are common to valvulogenic and osteogenic processes. These studies lend support to the idea that a developmental gene program is reactivated in aortic valve disease and may contribute to the molecular mechanisms underlying valve calcification in disease.

Figure 1. Diagram of embryonic valve development and valve maturation

(A) At mouse E10.5, immature cushions have formed in the atrioventricular (AV) canal and outflow tract (OFT). Endocardial derived cells populate the atrioventricular cushions (AVC) and portions of the OFT cushions (blue). Neural crest cells (NCC) (yellow) also contribute to the OFT cushions and aorticopulmonary septum (APS). (A’) Transcription factors including Twist1, Tbx20, Msx1, and Msx2 are important for AVC development. (B) At E13.5, the valve primordia (blue) begin remodeling and start to elongate. The dorsal mesenchymal protrusion (DMP) (purple) has fused with the AVC to form part of the atrial septum (AS). (B’) The transcription factors Sox9, Scleraxis, and Nfatc1 are important for valve remodeling. (C, D). The mature valves contain highly specialized extracellular matrix in three distinct layers, the collagenous fibrosa layer, the elastin-rich ventricularis/atrialis layers, and the proteoglycan abundant spongiosa layer. Ao= aorta, EC= endocardial cushions, EP= epicardium, EPDC= epicardial derived cells, IVS= interventricular septum, LA=left atrium, LV= left ventricle, RA= right atrium, RV= right ventricle.

Figure 2. The progression of AoV disease

(A) The normal aortic valve (AoV) is stratified into three highly specialized extracellular matrix (ECM) layers. The fibrosa layer is composed primarily of collagens, the spongiosa contains proteoglycans, and the ventricularis layer is rich in elastin. (B) Valvular interstitial cells (VIC) are activated during AoV disease, assuming a myofibroblast phenotype (red stars). (C) Valve sclerosis (orange) involves an overproduction of ECM molecules and maladaptive ECM remodeling, resulting in valve thickening. (D) Late stages of AoV disease are characterized by valve stenosis, which commonly involves valve calcification (black). Ao= aorta.