TRPV4 regulates β1 integrin-mediated cell-matrix adhesions and collagen remodeling

Transient Receptor Potential Vanilloid-type 4 (TRPV4) is a mechanosensitive, Ca2+-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 beta 11 integrin, it is not understood whether TRPV4 affects matrix remodeling by altering beta 11 integrin expression and function. We tested the hypothesis that TRPV4 regulates collagen remodeling through its impact on the beta 11 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 beta 11 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 beta 1 integrin expression mediated by TRPV4 is associated with the upregulation of miRNAs that target beta 1 integrin mRNA. Our data suggest a novel mechanism by which TRPV4 modulates collagen remodeling through post-transcriptional downregulation of beta 11 integrin expression and function.