Dynamic and static biomechanical traits of cardiac fibrosis

Abstract

Cardiac fibrosis is a common pathology in cardiovascular diseases which are reported as the leading cause of death globally. In recent decades, accumulating evidence has shown that the biomechanical traits of fibrosis play important roles in cardiac fibrosis initiation, progression and treatment. In this review, we summarize the four main distinct biomechanical traits (i.e., stretch, fluid shear stress, ECM microarchitecture, and ECM stiffness) and categorize them into two different types (i.e., static and dynamic), mainly consulting the unique characteristic of the heart. Moreover, we also provide a comprehensive overview of the effect of different biomechanical traits on cardiac fibrosis, their transduction mechanisms, and in-vitro engineered models targeting biomechanical traits that will aid the identification and prediction of mechano-based therapeutic targets to ameliorate cardiac fibrosis.

Keywords: biomechanical traits; cardiac fibrosis; mechanical model in vitro; mechanotransduction; myofibroblast.

FIGURE 1

The biomechanical traits of cardiac fibrosis. Schematic diagram of cardiac fibrosis ECM was drew online using Figdraw. According to recent progresses of biomechanics, we recommend respectively from two biomechanical types to understand cardiac fibrosis. The fibrotic area must be subjected to a stretch force because of the beating of the heart. The microarchitecture and the fluid shear stress are the mechanical stress contained and transmitted by the solid phase and the liquid phase, respectively. Stiffness is defined as the ability of a material to resist deformation under external forces. The physical interaction between cardiac cells and ECM produces the physical features of cardiac fibrosis through different and interrelated mechanisms. The abnormal contraction and relaxation of the heart cause vascular stretch to increase blood fluid pressure within the site of fibrosis. Cell differentiation, increased fluid shear stress, and matrix deposition result in compressive microarchitecture. Cardiac stretch, matrix deposition, and cross-linking can respectively lead to increased stiffness at the fibrotic site. The microarchitecture leads to the stretching and alignment of the matrix, and tissue stiffening increases the differentiation of cardiac fibroblasts. Fluid flow and excessive strain activate fibroblasts, which then contribute to increased cardiac wall stress and stiffness values and changes in ECM structure.

FIGURE 2

Signaling pathways associated with the biomechanical traits of cardiac fibrosis. With the changes of ECM mechanical properties during the process of cardiac fibrosis, myofibroblasts are activated . In classical signaling pathway, the TGF-β receptor’s activation induces phosphorylation of the C-terminus of SMAD. The phosphorylated SMADs then form a complex with the co-mediator SMAD, SMAD4, the complex is translocated into the nucleus, where it binds to the gene promoter. Upon myofibroblasts are activated, TGF-β is released from binding proteins in the ECM, leading to sustained activation and contraction of myofibroblasts, finally causing a vicious cycle of fibrotic progression. In addition, integrins which sense changes in external forces can also contribute to the remodeling of the cytoskeleton. Studies have shown that the activation of cell membrane surface mechanosensitive receptors (such as Piezo1, AT₁R and TRPV4) are also key pathways in the vicious cycle of fibrosis. Correlational studies have shown that Piezo1 can be activated by shear stress, stretching and matrix microarchitecture. Ang, Angiopoietin; TGF-β, transforming growth factor-beta; PDGF, plateau-derived growth factor; α-SMA, Piezo1, piezo type mechanosensitive ion channel component 1; alpha-smooth muscle actin; TGFβR, transforming growth factor-beta receptor; TRPV4, transient receptor potential vanilloid type 4; YAP, YES-related proteins; TAZ, transcriptional coactivator with PDZ-binding motif; AT1R, angiotensin type 1 receptor; TEAD, TEA domain transcription factors; SMAD, drosophila mothers against decapentaplegic.

FIGURE 3

Schematic of several in vitro models simulating the change of biomechanical traits. Schematic diagrams were drew online using Figdraw. (A) A schematic diagram of a stretch system to apply long-term cyclic stretch to cells. (B) A schematic diagram of the equipment, which can generate shear force and rotational shear force respectively to simulate the fluid shear stress in vitro. (C) A scalable microarchitecture-cultivation platform for engineering cardiac tissues. (D) A schematic diagram of cells cultured in different matrix stiffness in 2D and 3D.