Hemodynamic stress and extracellular matrix stiffness provide essential information for homeostatic regulation and functional adaptation on the physiological and pathological remodeling of myocytes. Previously, we have reported that transient receptor potential cation channel vanilloid-family type 2 (TRPV2) is a candidate of myocyte mechanosensor, and crucial for the maintenance of cardiac structure and function. Here, we show the role of TRPV2 in the physiological and pathological remodeling of myocytes. TRPV2-deficient neonatal cardiomyocytes exhibited no sarcomere formation, reduced Ca²⁺ contents of sarcoplasmic reticulum, or spontaneous beating, suggesting that TRPV2-dificiency affects myocyte maturation. The elimination of TRPV2 from juveniles showed the reduction of myofilaments and mildly chamber dilation in adult stage. Isolated myocytes from these mice showed the impaired Ca²⁺ handling with excitation-contraction coupling and contractile dysfunction. In hypertrophic response, increased actin-myosin cross-bridge formation enhance passive cardiomyocytes stiffness in the transverse direction. However, TRPV2-deficent hearts showed no change of myofilament protein expression and severe cardiac dysfunction to pressure-overload. Thus, TRPV2 is critical for compensate hypertrophic response to mechanical stress.