Cellular Mechanisms of Aortic Valve Calcification

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Cellular Mechanisms of Aortic Valve Calcification by Jane A. Leopold Circ Cardiovasc Interv Volume 5(4):605-614 August 14, 2012 Copyright © American Heart Association, Inc. All rights reserved.

Cellular architecture of the aortic valve. Cellular architecture of the aortic valve. Valve endothelial cells (VECs) line the outer surface of the valve and function as a barrier to limit inflammatory cell infiltration and lipid accumulation. The 3 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. Adapted from Rajamannan et al.10 Jane A. Leopold Circ Cardiovasc Interv. 2012;5:605-614 Copyright © American Heart Association, Inc. All rights reserved.

Spectrum of aortic valve calcification. Spectrum of aortic valve calcification. A, Gross anatomic specimen of a minimally diseased aortic valve demonstrating few nodules (left) and a 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, 100×. Reprinted with permission from Freeman and Otto.13 Jane A. Leopold Circ Cardiovasc Interv. 2012;5:605-614 Copyright © American Heart Association, Inc. All rights reserved.

Bone morphogenetic protein and Wnt signaling in valve interstitial cells (VICs). Bone morphogenetic protein and Wnt signaling in valve interstitial cells (VICs). Bone morphogenetic proteins (BMPs) 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. Jane A. Leopold Circ Cardiovasc Interv. 2012;5:605-614 Copyright © American Heart Association, Inc. All rights reserved.

Angiogenesis in a calcified valve. 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, 250×. Reprinted with permission from Mohler et al.15 Jane A. Leopold Circ Cardiovasc Interv. 2012;5:605-614 Copyright © American Heart Association, Inc. All rights reserved.

Key cellular mechanisms that promote aortic valve calcification. Jane A. Leopold Circ Cardiovasc Interv. 2012;5:605-614 Copyright © American Heart Association, Inc. All rights reserved.