TRPV4 integrates matrix mechanosensing with Ca²⁺ signaling to regulate extracellular matrix remodeling

In healthy connective tissues, mechanosensors trigger the generation of Ca²⁺ signals, which enable cells to maintain the structure of the fibrillar collagen matrix through actomyosin contractile forces. Transient receptor potential vanilloid type 4 (TRPV4) is a mechanosensitive Ca²⁺ -permeable channel that, when expressed in cell-matrix adhesions of the plasma membrane, regulates extracellular matrix (ECM) remodeling. In high prevalence disorders such as fibrosis and tumor metastasis, dysregulated matrix remodeling is associated with disruptions of Ca²⁺ homeostasis and TRPV4 function. Here, we consider that ECM polymers transmit cell-activating mechanical signals to TRPV4 in cell adhesions. When activated, TRPV4 regulates fibrillar collagen remodeling, thereby altering the mechanical properties of the ECM. In this review, we integrate functionally connected processes of matrix remodeling to highlight how TRPV4 in cell adhesions and matrix mechanics are reciprocally regulated through Ca²⁺ signaling.