TRPV4 regulates β1 integrin‐mediated cell–matrix adhesions and collagen remodeling

Abstract

Transient Receptor Potential Vanilloid-type 4 (TRPV4) is a mechanosensitive, Ca 2+ -permeable plasma membrane channel that associates with focal adhesions, influences collagen remodeling, and is associated with fibrotic processes through undefined mechanisms. While TRPV4 is known to be activated by mechanical forces transmitted through collagen adhesion receptors containing the β1 integrin, it is not understood whether TRPV4 affects matrix remodeling by altering β1 integrin expression and function. We tested the hypothesis that TRPV4 regulates collagen remodeling through its impact on the β1 integrin in cell-matrix adhesions. In cultured fibroblasts derived from mouse gingival connective tissues, which exhibit very rapid collagen turnover, we found that higher TRPV4 expression is associated with reduced β1 integrin abundance and adhesion to collagen, reduced focal adhesion size and total adhesion area, and reduced alignment and compaction of extracellular fibrillar collagen. The reduction of β1 integrin expression mediated by TRPV4 is associated with the upregulation of miRNAs that target β1 integrin mRNA. Our data suggest a novel mechanism by which TRPV4 modulates collagen remodeling through post-transcriptional downregulation of β1 integrin expression and function.

Impact of TRP Channels on Extracellular Matrix Remodeling: Focus on TRPV4 and Collagen

“…Studies conducted of cultured cells show that, upon integrin binding and activation by ECM ligands, the cytoplasmic domains of integrins participate in the assembly of cell adhesions, which are termed focal adhesions. There is increased interest in the role of focal adhesions and other types of cell adhesions as they directly impact ECM structure, function, and remodeling, and their structure is influenced by TRPV4 expression [59]. Proteins that associate with the cytoplasmic domains of integrins in focal adhesions include actin binding proteins, such as talin, paxillin, non-muscle myosin, filamins and α-actinins, and signaling proteins (e.g., focal adhesion kinase and Src kinases [60]).…”

“…Unexpectedly, high levels of TRPV4 expression are associated with reduced β1 integrin abundance and adhesion to collagen, reduced cell adhesion area, and reduced alignment and compaction of extracellular fibrillar collagen. This reduction of β1 integrin expression, driven by TRPV4, is dependent on the upregulation of microRNAs that target β1 integrin mRNA and affect the abundance of β1 integrin transcripts [59]. Expression levels of TRPV4 also affect the size and relative numbers of focal adhesions and the organization of actin-binding proteins in cell adhesions [59], indicating a regulatory role for TRPV4 in the function of adhesive organelles and, potentially, in ECM turnover.…”

“…The effect of cyclosporin A on gingival overgrowth is associated with alterations in intracellular Ca 2+ signaling [66], which affect intracellular degradation of collagen in lysosomes and then promote the accumulation of collagen in gingival tissues. The recent identification of TRPV4 channels in human gingival fibroblasts and the impact of these channels on collagen remodeling [59] suggest the possibility that some of these gingival overgrowth-promoting drugs may affect TRPV4 function.…”