Electro-mechanical coupling directs endothelial activities through intracellular calcium ion deployment†

Conversion between mechanical and electrical cues is usually considered unidirectional in cells with cardiomyocytes being an exception. Here, we discover a material-induced external electric field (E_ex) triggers an electro-mechanical coupling feedback loop in cells other than cardiomyocytes, human umbilical vein endothelial cells (HUVECs), by opening their mechanosensitive Piezo1 channels. When HUVECs are cultured on patterned piezoelectric materials, the materials generate E_ex (confined at the cellular scale) to polarize intracellular calcium ions ([Ca²⁺]_i), forming a built-in electric field (E_in) opposing E_ex. Furthermore, the [Ca²⁺]_i polarization stimulates HUVECs to shrink their cytoskeletons, activating Piezo1 channels to induce influx of extracellular Ca²⁺ that gradually increases E_in to balance E_ex. Such an electro-mechanical coupling feedback loop directs pre-angiogenic activities such as alignment, elongation, and migration of HUVECs. Activated calcium dynamics during the coupling further modulate the downstream angiogenesis-inducing eNOS/NO pathway. These findings lay a foundation for developing new ways of electrical stimulation-based disease treatment.