From Biomechanical Mechanisms to Clinical Reasoning: Deciphering Mechanobiological Drivers of Aortic Valve Calcification for Precision Therapy

Fig. 1. Hemodynamic forces experienced by aortic valves during systolic and diastolic phases This schematic illustrates the dynamic mechanical microenvironment of native aortic valve leaflets during systole and diastole. During systole, the aortic valve opens and blood is ejected from the left ventricle into the aorta; the leaflets are simultaneously subjected to four major mechanical stimuli: transvalvular pressure, laminar shear stress, oscillatory shear stress, and cyclic circumferential stretch. During diastole, the aortic valve closes to prevent blood regurgitation, and the closed leaflets primarily bear sustained transvalvular pressure and tensile stress. The magnified inset depicts the spatial distribution of VECs lining the leaflet surface and VICs embedded within the leaflet matrix, and indicates the direction and distribution pattern of various mechanical loads acting on different cellular layers. This figure delineates the physiological mechanical microenvironment of the aortic valve throughout the cardiac cycle, providing a physiological biomechanical baseline for investigating the mechanobiological mechanisms underlying calcific aortic valve disease (CAVD). Schematic created…

Fig. 2. Traditional chemical signaling pathways involved in mechanobiology affecting CAVD This figure systematically presents two types of initiating mechanical injuries and their downstream chemical signaling cascades that drive the progression of calcific aortic valve disease (CAVD), which are interconnected and mutually reinforced via a positive feedback loop. Hemodynamic abnormalities can be either triggered by initiating factors such as bicuspid aortic valve malformation and hypertension, or occur secondarily during disease progression. Increased extracellular matrix (ECM) stiffness can likewise represent an initiating change mediated by etiologies such as Marfan syndrome, or arise secondary to disease progression. Abnormal blood flow promotes increased ECM stiffness, which in turn exacerbates hemodynamic abnormalities and drives their progression. The two thereby form a self-reinforcing positive feedback loop that collectively accelerates the disease course of CAVD. Disturbed hemodynamic mechanical signals induce the activation of VECs and potential endothelial-to-mesenchymal transition (EMT), accompanied by an imbalance between cell proliferation and apoptosis. In VICs, these…

Fig. 3. Mechanical force signaling pathways mediated by cytoskeletal proteins involved in mechanobiology affecting CAVD This schematic demonstrates the direct mechanotransduction axis through which extracellular mechanical forces are transmitted from the cell surface to the nucleus to regulate target gene expression in calcific aortic valve disease (CAVD). Extracellular mechanical forces are first sensed by the transmembrane integrin αvβ3 receptor, and then propagated intracellularly via the F-actin cytoskeleton and myosin Ⅱ. The mechanical signals further traverse the nuclear envelope through components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, namely Nesprins and inner nuclear membrane proteins, and are transmitted to lamins and intranuclear SUN proteins. This physical force transmission process remodels the spatial conformation of chromatin and regulates the expression of target genes related to osteogenic differentiation and ECM remodeling via intranuclear mediators such as BAF and HP1. This "cytoskeleton–nucleus" mechanical coupling constitutes a direct mechanotransduction pathway independent of chemical messengers, which converts extracellular biomechanical…