Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives

Abstract

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived "matrix vesicles" and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.

Keywords: calcific aortic valve disease; collagen; elastic fibers; extracellular matrix; extracellular vesicles; periostin; tenascin-C.

Figure 1

Schematic representation of Calcific Aortic Valve Disease (CAVD) pathogenesis. Collagen is the predominant component of the fibrosa in healthy cardiac valves, while the spongiosa and ventricularis are mainly composed of proteoglycans (PGs) and a collagen/elastin network, respectively. (A) Initial lesions, such as endothelial damage, account for the recruitment of inflammatory elements in the valve, triggering initial microcalcification. Resident cells such as VICs and VECs as well as circulating macrophages support the calcification process via the release of extracellular vesicles. Apoptotic myofibroblasts and immunity cells favor nucleation of calcium and phosphate. The resulting inflammatory microenvironment and myofibroblasts differentiation cause extracellular matrix (ECM) remodeling, valve thickening and fibrosis. Further differentiation in osteoblasts accounts for calcification, remodeling and biomineralization or ossification. Ectopic expression of TNC is also depicted. (B) Hypoxic conditions induce the formation of new ectopic vessels which in turn support ECM remodeling via MMP- and cathepsins-dependent degradation of collagen and elastic fibers, respectively. (C) The activation of the SDF-1/CXCR4 pathway in endothelial cells further stimulates the homing of inflammatory elements (C). CXCR4, C-X-C Motif Chemokine Receptor 4; EVs, extracellular vesicles; GAG, glycosaminoglycans; SDF-1, stromal cell-derived factor 1; TNC, tenascin-C; MMPs, matrix metalloproteinases; VECs, valve endothelial cells; VEGF, vascular endothelial growth factor; VICs, vascular interstitial cells.

Figure 1

Schematic representation of Calcific Aortic Valve Disease (CAVD) pathogenesis. Collagen is the predominant component of the fibrosa in healthy cardiac valves, while the spongiosa and ventricularis are mainly composed of proteoglycans (PGs) and a collagen/elastin network, respectively. (A) Initial lesions, such as endothelial damage, account for the recruitment of inflammatory elements in the valve, triggering initial microcalcification. Resident cells such as VICs and VECs as well as circulating macrophages support the calcification process via the release of extracellular vesicles. Apoptotic myofibroblasts and immunity cells favor nucleation of calcium and phosphate. The resulting inflammatory microenvironment and myofibroblasts differentiation cause extracellular matrix (ECM) remodeling, valve thickening and fibrosis. Further differentiation in osteoblasts accounts for calcification, remodeling and biomineralization or ossification. Ectopic expression of TNC is also depicted. (B) Hypoxic conditions induce the formation of new ectopic vessels which in turn support ECM remodeling via MMP- and cathepsins-dependent degradation of collagen and elastic fibers, respectively. (C) The activation of the SDF-1/CXCR4 pathway in endothelial cells further stimulates the homing of inflammatory elements (C). CXCR4, C-X-C Motif Chemokine Receptor 4; EVs, extracellular vesicles; GAG, glycosaminoglycans; SDF-1, stromal cell-derived factor 1; TNC, tenascin-C; MMPs, matrix metalloproteinases; VECs, valve endothelial cells; VEGF, vascular endothelial growth factor; VICs, vascular interstitial cells.