Cell–Matrix Interactions in the Pathobiology of Calcific Aortic Valve Disease

Abstract

The hallmarks of calcific aortic valve disease (CAVD) are the significant changes that occur in the organization, composition, and mechanical properties of the extracellular matrix (ECM), ultimately resulting in stiffened stenotic leaflets that obstruct flow and compromise cardiac function. Increasing evidence suggests that ECM maladaptations are not simply a result of valve cell dysfunction; they also contribute to CAVD progression by altering cellular and molecular signaling. In this review, we summarize the ECM changes that occur in CAVD. We also discuss examples of how the ECM influences cellular processes by signaling through adhesion receptors (matricellular signaling), by regulating the presentation and availability of growth factors and cytokines to cells (matricrine signaling), and by transducing externally applied forces and resisting cell-generated tractional forces (mechanical signaling) to regulate a wide range of pathological processes, including differentiation, fibrosis, calcification, and angiogenesis. Finally, we suggest areas for future research that should lead to new insights into bidirectional cell-ECM interactions in the aortic valve, their contributions to homeostasis and pathobiology, and possible targets to slow or prevent the progression of CAVD.

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

“…Recently it was highlighted that despite an abundance of proteglycans and GAGs in valves in CAVD the role of proteoglycans and GAGs has not been investigated [31]. Our study demonstrates that in porcine VICs TGF-β1 weakly induces proteoglycan core protein synthesis, and strongly stimulates proteoglycan GAG chain elongation.…”

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

“…Extracellular remodeling is a key process in CAVD (Chen and Simmons 2011) and has long been regarded as a result of inflammation (Kaden et al 2005). Matrix metalloproteinases (MMPs) can contribute to the initial loss of collagen, damages in endothelial integrity, extracellular matrix remodeling, exacerbating inflammation and, finally, inducing valve calcification (Nissinen and Kahari 2014;Pasipoularides 2016).…”

The pathology and pathobiology of bicuspid aortic valve: State of the art and novel research perspectives

“…Also, oxidised‐low density lipoprotein (ox‐LDL) increases the synthesis of dermatan sulfate, which enhances the bioavailability of TGF‐β1 31. Although the molecular mechanism is not clearly delineated, it is possible that the addition of GAG chain inhibits the normal sequestration of TGF‐β1 by decorin 32.…”