Cellular mechanisms of aortic valve calcification

Abstract

Acquired aortic valve disease and valvular calcification is highly prevalent in adult populations worldwide and is associated with significant cardiovascular morbidity and mortality. At present, there are no medical therapies that will prevent or regress aortic valve calcification or stenosis and surgical or transcatheter aortic valve replacement remain the only effective therapies for treating this disease. In the setting of valve injury as a result of exposure to biochemical mediators or hemodynamic forces, normal homeostatic processes are disrupted resulting in extracellular matrix degradation, aberrant matrix deposition and fibrosis, inflammatory cell infiltration, lipid accumulation, and neoangiogenesis of the valve tissue and, ultimately, calcification of the valve. Calcification of the aortic valve is now understood to be an active process that involves the coordinated actions of resident valve endothelial and interstitial cells, circulating inflammatory and immune cells, and bone marrow-derived cells. These cells may undergo a phenotype transition to become osteoblast-like cells and elaborate bone matrix, endothelial-to-mesenchymal transition, and form matrix vesicles that serve as a nidus for microcalcifications. Each of these mechanisms has been shown to contribute to aortic valve calcification suggesting that strategies that target these cellular events may lead to novel therapeutic interventions to halt the progression or reverse aortic valve calcification.

Figure 1

Cellular architecture of the aortic valve. Valve endothelial cells (VECs) line the outer surface of the valve and functions as a barrier to limit inflammatory cell infiltration and lipid accumulation. The three middle layers of the valve are the fibrosa, spongiosa, and ventricularis. These layers contain valve interstitial cells (VICs) as the predominant cell type. The fibrosa is nearest the aortic side of the valve, contains type I and type III fibrillar collagen, and serves a load-bearing function. The spongiosa contains glycosaminoglycans (GAGs) that lubricate the fibrosa and ventricularis layers as they shear and deform during the cardiac cycle. The ventricularis contains elastin fibers to decrease radial strain.

Figure 2

Spectrum of aortic valve calcification. A) Gross anatomic specimen of a minimally diseased aortic valve demonstrating few nodules (left) and severely diseased calcified valve with evidence of nodular calcifications (arrow) on the valve cusps (right). B) Histological findings in the early stages of valve calcification include abundant subendothelial lipid and extracellular matrix with displacement of the elastic lamina (arrow)(left). As the disease progresses, lipid, cells, and extracellular matrix are increased with evidence of breakdown and displacement of the elastic lamina (arrow). Verhoff-van Gieson stain, 100X. Reprinted with permission from .

Figure 3

Bone morphogenetic protein and Wnt signaling in VICs. Bone morphogenetic proteins (BMP) bind to the bone morphogenetic protein receptor (BMPR) to phosphorylate (P) and activate Smad signaling. Smad signaling increases transcription of the osteoblast transcription factor Runx2, which leads to upregulation of Runx2-dependent calcification proteins. Smad signaling also increases expression of Msx2 and participates in β-catenin-mediated gene transcription. BMPs also promote Wnt signaling. Wnt ligands bind to receptor complexes of frizzled protein/lipoprotein receptor-related protein (LRP) 5 or 6 to activate β-catenin signaling and upregulate expression of alkaline phosphatase. Together these signaling pathways promote transition of VICs to osteoblast-like cells that are able to calcify in the presence of phosphate and calcium. VICs, valve interstitial cells.

Figure 4

Angiogenesis in a calcified valve. In calcifying valves, there is evidence of angiogenesis with the numerous vessels (V) in the valve. These vessels are located near an area of calcification (CA). Hematoxylin and eosin, 250X. Reprinted with permission from .

Figure 5

Key cellular mechanisms that promote aortic valve calcification.