This study provides several findings of novelty and special relevance: (1) TRPV4 channels mediate the development of pathological, but not physiological, remodeling, introducing a new differential element between both types of response; (2) during the development of HF, TRPV4 upregulation is associated with Ca2+-dependent activation of the CN/NFATc3 pathway in cardiac FB and secondary fibrosis; (3) TRPV4 activation during HF induces the upregulation of TRPC6, initiating a circuit of positive feedback that further enhances the maladaptive response in cardiac FB. This evidence concerns the gene TRPV4 and hydrops fetalis.