The Genetic Regulation of Aortic Valve Development and Calcific Disease

Vinal Menon, Joy Lincoln, Vinal Menon, Joy Lincoln

Abstract

Heart valves are dynamic, highly organized structures required for unidirectional blood flow through the heart. Over an average lifetime, the valve leaflets or cusps open and close over a billion times, however in over 5 million Americans, leaflet function fails due to biomechanical insufficiency in response to wear-and-tear or pathological stimulus. Calcific aortic valve disease (CAVD) is the most common valve pathology and leads to stiffening of the cusp and narrowing of the aortic orifice leading to stenosis and insufficiency. At the cellular level, CAVD is characterized by valve endothelial cell dysfunction and osteoblast-like differentiation of valve interstitial cells. These processes are associated with dysregulation of several molecular pathways important for valve development including Notch, Sox9, Tgfβ, Bmp, Wnt, as well as additional epigenetic regulators. In this review, we discuss the multifactorial mechanisms that contribute to CAVD pathogenesis and the potential of targeting these for the development of novel, alternative therapeutics beyond surgical intervention.

Keywords: aortic valve calcification; development; epigenetics; extracellular matrix; hemodynamics; signaling; valve endothelial cell; valve interstitial cell.

Figures

Figure 1
Figure 1
Schematic representation of a healthy and calcified aortic valve cusp. Cross sectional representation of a heart highlighting the aortic valve (box). (A) A healthy aortic valve cusp structure consists of three layers of extracellular matrix (ECM); the ventricularis (elastin fibers, black); the spongiosa (proteoglycans, blue); and the fibrosa (collagens, yellow). In addition to the matrix, the valve cusp is encapsulated by a single layer of valve endothelial cells (VECs), while valve interstitial cells (VICs) populate the core of the cusp. (B) A calcified valve cusp is thickened with abrogations in ECM organization including fragmented elastin fibers and increased collagen content. In addition, calcific nodules form on the fibrosa surface of the cusp (off-white).
Figure 2
Figure 2
Molecular communications between VEC and VIC populations. (A) Schematic to show known signaling pathways active between VEC and VIC populations that prevent CAVD. (B) Diagram to demonstrate known cellular functions regulated by VEC-VIC communications; the mechanisms underlying these functions are currently unknown, based on studies by Hjortnaes et al. (140). Purple cells represent valve endothelial cells, blue cells are valve interstitial cells.

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