TRPV4 Mechanotransduction in Fibrosis

Abstract

Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis.

Ion Channels in the Development and Remodeling of the Aortic Valve

“…Indeed, stretch-induced increase in collagen I synthesis by human VIC in culture is reduced by the pharmacological TRPV4 inhibitor RN 9398 [ 55 ]. More generally, TRPV4 was shown to be implicated in several models of fibroblast mechano-sensitivity [ 63 ]. Its role in valvular stiffness-induced myofibroblastic activation was also investigated in a model of isolated porcine VIC in culture [ 56 ].…”

“…Thus, other proteins would allow the TRPV4 mechano-sensitivity, for example, interactions with cytoskeletal or external proteins. β1-integrin might be a good candidate since it was shown in bovine capillary endothelial cells that TRPV4 is activated by mechanical forces through β1-integrin cytoplasmic tail binding protein CD98 [ 63 , 66 ]. While not demonstrated in VIC, this process is, however, plausible since β1-integrin was detected in porcine VIC in culture [ 67 ].…”

The Role of Myofibroblasts in Physiological and Pathological Tissue Repair

“…2B). While most earlier studies investigated these receptors in cardiac and pulmonary (myo)fibroblasts (Rahaman et al 2014;Arora et al 2017;Bhattacharya and Hough 2019;Blythe et al 2019;Grove et al 2019;Dutta et al 2020;Adapala et al 2021;Stewart and Turner 2021), they have recently also attracted attention in the context of cutaneous wound healing (Anderson et al 2017;He et al 2021;Holt et al 2021). For instance, Piezo1 plays an important role in detecting ECM elasticity and regulating cell behavior related to hypertrophic scarring (He et al 2021).…”

“…FAK inhibitors have not been tested yet in clinical trials for the treatment of fibrosis. In addition, inhibition of mechanosensitive fibroblast membrane channels like Piezo1 and TRPV4 and gap junction components such as connexin 43 are being pursued to treat "channelopathies" like those causing cardiac dysfunction (Andelova et al 2020;Jiang et al 2021;Lawhorn et al 2021) These compounds have not yet been tested in the clinical treatment of organ fibrosis (Rahaman et al 2014;Inoue et al 2019;Prakoura et al 2019;Adapala et al 2021;Fu et al 2021b;Stewart and Turner 2021) and are just beginning to be considered for wound healing therapies (Becker et al 2016;Montgomery et al 2018;He et al 2021). As inhibitors of these receptors, only the TRPV4 channel blocker GSK2798745 has advanced to clinical trials targeting pulmonary edema in congestive heart failure (NCT02497937) but not fibrosis.…”

Mechanotransduction in skin wound healing and scar formation: Potential therapeutic targets for controlling hypertrophic scarring

“…Calcium influx via transient receptor potential (TRP) channels has been found to play a crucial role in response to mechanical input ( 107 ). TRP channels are divided into six subfamilies, including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin), and TRPML (mucolipin) ( 108 ). Several of them are potential mechanical force transducers that participate in HTS formation.…”