The study of Piezo channels has significantly advanced our understanding of mechanotransduction in various biological systems, including the cardiovascular system. These channels, particularly Piezo1, have been implicated in a range of physiological and pathological processes, such as heart function, vascular tone regulation, and response to mechanical stress. Despite their crucial role in cardiovascular health, several challenges remain in fully elucidating the mechanisms by which Piezo channels mediate heart function. This review explores the frontiers of Piezo channel research, with a focus on the challenges that hinder progress and potential future directions.

Piezo channels, mechanotransduction, cardiac function

LTP: long-term potentiation

Mechanotransduction and Piezo Channels

Mechanotransduction is the process by which cells sense and respond to mechanical stimuli, a key function in many tissues, including the heart. Piezo1 is a mechanosensitive ion channel that plays a critical role in translating mechanical forces into biochemical signals. It is expressed in various cardiac cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells, where it helps regulate cell proliferation, migration, and contraction in response to mechanical stress.

Piezo1 in cardiac mechanotransduction

Piezo1 channels are integral to the mechanotransduction pathways in the cardiovascular system. They mediate the flow of ions across the membrane in response to stretch or pressure, influencing the electrical properties and contractile behavior of heart cells. Recent work has emphasized the importance of Piezo1 in regulating cardiac rhythm, with mutations in Piezo1 contributing to arrhythmias and heart failure.

Research has significantly advanced our understanding of Piezo1’s role in mechanotransduction. A pivotal study [1] highlights the critical role of Piezo1 in neurogenesis and cognitive functions. The paper demonstrates that Piezo1 deficiency in astrocytes leads to impaired hippocampal long-term potentiation (LTP) and cognitive dysfunction, while overexpression of Piezo1 enhances these processes. These findings underscore the importance of Piezo1 in regulating mechanotransduction in neurogenic niches, which could have significant implications for understanding how mechanotransduction influences other systems, such as the cardiovascular system.

Key findings from research on Piezo1

1. Piezo1 deficiency in mice: Mice deficient in Piezo1 exhibit impaired hippocampal LTP and significant deficits in learning and memory, providing evidence for the essential role of Piezo1 in brain function.
2. Overexpression of Piezo1: In contrast, enhancing Piezo1 expression in astrocytes results in improved mechanotransduction, which enhances cognitive performance and neurogenesis. These findings may suggest potential therapeutic strategies for enhancing mechanotransduction in diseases involving impaired cellular mechanosensing, including cardiovascular diseases.
3. Mechanotransduction in heart cells: The insights gained from research on Piezo1-mediated mechanotransduction in astrocytes can be applied to cardiac cells. Just as Piezo1 affects cognitive function through mechanotransduction in the brain, it may similarly impact heart function by influencing cellular responses to mechanical stimuli.

Despite these advances, several technological hurdles remain in studying Piezo1 and its role in cardiovascular function:

1. Structural complexity: The three-dimensional structure of Piezo1, with its intricate mechanical gating mechanism, poses challenges for researchers attempting to understand its precise function. While studies such as Zhao et al. [2] have provided valuable insights into the structure and mechanogating mechanisms of Piezo1, the full picture is still far from complete [2–7].
2. Functional variability: Piezo1’s function is influenced by various factors, including cell type, tissue environment, and mechanical force. This functional variability complicates the interpretation of experimental results and the development of therapeutic strategies targeting Piezo1.
3. Technology for monitoring mechanotransduction: Current technologies for studying mechanotransduction are limited by resolution and sensitivity. Advanced techniques, such as high-resolution imaging and single-molecule force spectroscopy, are needed to study Piezo1 channels in real-time and under physiological conditions.

Mutations in Piezo1 have been linked to various cardiovascular diseases. For example, mutations that impair Piezo1 function can lead to arrhythmias and vascular abnormalities. Research by Sun et al. [8] demonstrated that Piezo1 plays a critical role in bone formation, with mutations in Piezo1 disrupting osteogenesis and bone strength. Similar mechanisms may be at play in the heart, where mutations in Piezo1 could affect the mechanosensitive signaling pathways that regulate cardiac cell function [8, 9].

The future of Piezo channel research holds great promise in understanding its role in heart function and disease. Some promising directions for future research include:

1. Piezo1 in cardiac arrhythmias: Further research is needed to determine the specific mutations in Piezo1 that contribute to arrhythmias and other cardiac diseases. Understanding how these mutations affect mechanotransduction and cellular signaling could provide new avenues for therapeutic interventions.
2. Therapeutic modulation of Piezo1: Based on findings that enhancing Piezo1 expression improves cognitive function, similar approaches could be explored for heart diseases. Modulating Piezo1 expression or activity could potentially restore normal mechanotransduction in diseased heart tissues.
3. Interdisciplinary research: Drawing on insights from work on Piezo1 in the brain, interdisciplinary collaborations between cardiac and neuroscience researchers could yield new strategies for treating cardiovascular diseases involving mechanotransduction defects.

Piezo1 channels play a pivotal role in mechanotransduction in both the brain and the heart, with research significantly contributing to our understanding of these mechanisms. The work on Piezo1-mediated mechanotransduction in astrocytes provides valuable insights that can be applied to heart research, particularly in understanding how mutations in Piezo1 lead to heart dysfunction. While significant challenges remain in studying Piezo1’s function, recent technological advances and growing research into Piezo1’s role in mechanotransduction offer promising directions for future therapeutic strategies in cardiovascular diseases.

Chi S wrote the manuscript.

This work was supported by the Australian Research Council (ARC, DE230101128).

1. Chi S, Cui Y, Wang H, et al. Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions. Neuron. 2022;110(18):2984-999.e8.
2. Zhao Q, Zhou H, Chi S, et al. Structure and mechanogating mechanism of the Piezo1 channel. Nature. 2018;554(7693):487-92.
3. Zhao Q, Wu K, Geng J, et al. Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels. Neuron. 2016;89(6):1248-263.
4. Zhang T, Chi S, Jiang F, et al. A protein interaction mechanism for suppressing the mechanosensitive Piezo channels. Nat Commun. 2017;8(1):1797.
5. Chi S. A protein interaction mechanism for suppressing the mechanosensitive piezo channels. Biophys J. 2018;114(3):111a.
6. Wang Y, Chi S, Guo H, et al. A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. Nat Commun. 2018;9(1):1300.
7. Wang Y, Chi S, Zhao Q, et al. A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. Biophys J. 2018;114(3):113a–114a.
8. Sun W, Chi S, Li Y, et al. The mechanosensitive Piezo1 channel is required for bone formation. Elife. 2019;8:e47454.
9. Zhao Q, Wu K, Chi S, et al. Heterologous Expression of the Piezo1-ASIC1 Chimera Induces Mechanosensitive Currents with Properties Distinct from Piezo1. Neuron. 2017;94(2):274-77.