Essential Roles of PIEZO1 in Mammalian Cardiovascular System: From Development to Diseases

Abstract

Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications.

Keywords: PIEZO1; cardiovascular system; chemical therapies; development; diseases; homeostasis; mechanotransduction.

Figure 1

Schematic diagram of PIEZO1 structure and mechanogating mechanism. (A) PIEZO1 in a resting state. (B) PIEZO1 in an activated state. IH: inner helices, OH: outer helix.

Figure 2

Schematic diagram of the mechanisms by which PIEZO1 promotes vascular development and homeostasis in vascular endothelial cells (VECs). Solid arrows indicate promotion and dashed arrows indicate suppression. ADAM10: Ca²⁺-dependent transmembrane abscission enzyme, ICAM-1: intercellular cell adhesion molecule-1, KLF2/4: kruppel-like factor 2/4, MT1-MMP: membrane-type matrix metalloproteinase 1, PCAM-1: CD31, RBPJ: recombination signal binding protein for immunoglobulin kappa J region, THBD: thrombomodulin, VCAM-1: vascular cell adhesion molecule-1, VE-cadherin: vascular endothelial cadherin, VEGF: endothelial growth factor, VEGFR2: vascular endothelial growth factor receptor 2.

Figure 3

Schematic diagram of the mechanisms by which PIEZO1 promotes atherosclerosis (AS). (A) PIEZO1 in vascular endothelial cells (VECs). FAK: focal adhesion kinase, ITGα5: integrin alpha 5, JNK: c-Jun N-terminal kinase, NF-κB: nuclear factor-κ-gene binding, OX-LDL: oxidized low-density lipoprotein, TAZ: transcription coactivator with PDZ-binding motif, YAP: yes-associated protein. (B) PIEZO1 in vascular smooth muscle cells (VSMCs). ITGβ1: integrin beta 1, Mito: mitochondrion, NFAT5: nuclear factor of activated T-cells, PDGF: platelet-derived growth factor, ROS: reactive oxygen species, VEGF: endothelial growth factor. (C) PIEZO1 in macrophages (Mø). IL: interleukin, TNF-α: tumor necrosis factor-α.

Figure 4

Schematic diagram of the mechanisms by which PIEZO1 promotes vascular remodeling. The left cell diagram represents PIEZO1 in vascular smooth muscle cells (VSMCs); the right cell diagram represents PIEZO1 in vascular endothelial cells (VECs). DLL-4: delta like-4, IL-33: interleukin-33, JAG-1/2: jagged1/2, NF-κB: nuclear factor-κ-gene binding, ST2: suppression of tumorigenicity 2, YAP: yes-associated protein.

Figure 5

Schematic diagram of the mechanisms by which PIEZO1 promotes pathological myocardial hypertrophy and cardiac fibrosis. (A) PIEZO1 in pathological myocardial hypertrophy. CaM: calmodulin, CaMKII: calcium/calmodulin-dependent protein kinase II, CaN: calcineurin, CMs: cardiomyocytes, HDAC4: histone deacetylase 4, MEF2: myocyte enhancer factor 2, TRPM4: transient receptor potential melastatin 4. (B) PIEZO1 in cardiac fibrosis. FBs: fibroblasts, FAK: focal adhesion kinase, IL-6: interleukin-6, TNC: tenascin C.

Figure 6

Schematic diagram of active sites and regulators of PIEZO1.