Biology and Biomechanics of the Heart Valve Extracellular Matrix

Abstract

Heart valves are dynamic structures that, in the average human, open and close over 100,000 times per day, and 3 × 10⁹ times per lifetime to maintain unidirectional blood flow. Efficient, coordinated movement of the valve structures during the cardiac cycle is mediated by the intricate and sophisticated network of extracellular matrix (ECM) components that provide the necessary biomechanical properties to meet these mechanical demands. Organized in layers that accommodate passive functional movements of the valve leaflets, heart valve ECM is synthesized during embryonic development, and remodeled and maintained by resident cells throughout life. The failure of ECM organization compromises biomechanical function, and may lead to obstruction or leaking, which if left untreated can lead to heart failure. At present, effective treatment for heart valve dysfunction is limited and frequently ends with surgical repair or replacement, which comes with insuperable complications for many high-risk patients including aged and pediatric populations. Therefore, there is a critical need to fully appreciate the pathobiology of biomechanical valve failure in order to develop better, alternative therapies. To date, the majority of studies have focused on delineating valve disease mechanisms at the cellular level, namely the interstitial and endothelial lineages. However, less focus has been on the ECM, shown previously in other systems, to be a promising mechanism-inspired therapeutic target. Here, we highlight and review the biology and biomechanical contributions of key components of the heart valve ECM. Furthermore, we discuss how human diseases, including connective tissue disorders lead to aberrations in the abundance, organization and quality of these matrix proteins, resulting in instability of the valve infrastructure and gross functional impairment.

Keywords: collagen; connective tissue disorders; elastin; extracellular matrix; heart valve; proteoglycan.

Figure 1

Representation of aortic and mitral valve structure. (Left) Aortic (A) and Mitral (B) valve structures to show organization of three ECM layers, including the ventricularis (elastin), spongiosa (PGs-GAGs) and fibrosa (collagens). Each layer is arranged according to blood flow as indicated by red arrows (ventricularis/atrialis closest to blood flow). Overlying the valve leaflets (mitral) or cusps (aortic) is a single layer of valve endothelial cells (VECs, purple), while a population of valve interstitial cells (VICs, blue) are embedded within the core. (Right) Representation of the aortic valve indicating coordinated rearrangement of the ECM fibers, and elongation of the VICs during systole (open) and diastole (closed).

Figure 2

ECM-VIC Signaling Interactions. (A) Matricellular and mechanical signaling occurs in a force-, ligand-, and integrin heterodimer-specific manner. Once active, integrin heterodimer complex leads to activation of downstream pathways mediated by activation of signaling molecules, including focal adhesion kinase (FAK) and integrin-linked kinase (ILK). (B) During matricrine signaling in heart valves, metalloproteases (MMP) degrade structural components of the ECM, which allow signaling molecules such as cytokines, chemokines, and TGF-β to be released. Once activated by TGF-β, TGF-β receptors result in transcription of pro-fibrotic and pro-inflammatory genes via canonical or non-canonical TGF-β signaling cascade in VICs.