Cardiac mechanotransduction from development to disease

Mechanical cues control key aspects of cardiac structure formation and function from heart development through adult life. Because the heart is a pump, forces from muscle contraction and blood flow generate normal and shear stresses that, together with matrix stiffness, regulate cell fate, growth, and homeostasis through mechanotransduction. This review describes how mechanosensors in cardiomyocytes, endothelial cells, and fibroblasts, including integrins and stretch-activated ion channels, couple mechanical stimuli to their cellular responses. We outline pathways that translate force into key phenotypes relevant to morphogenesis, homeostasis, and disease progression, with emphasis on RhoA/ROCK, calcium, and Yes-associated protein (YAP) signaling. We also explain how elevated mechanical load driven by hypertension activates hypertrophic and fibrotic remodeling of cardiac chambers, particularly through transforming growth factor-β, integrins, YAP, and calcineurin signaling. Finally, we highlight emerging roles for mechanosensitive microRNAs in coordinating proliferation, metabolism, electrophysiology, and extracellular matrix dynamics in the heart. Since most, if not all, of these pathways are interconnected, a comprehensive understanding will require high-resolution maps of cardiac mechanical environments and clear links between defined stimuli and cell-type-specific responses. These insights will advance fundamental understanding and guide the development of more effective therapeutic strategies.