Feeling the pressure: TRPV4's mechanosensitive side

Mechanical and osmotic forces play a vital role in functional cardiac physiology [1]. It is widely accepted that the heart not only functions as a pump, but also a mechanosensitive organ, responding to alterations in the cellular environment. This study, investigating the role of the Transient Receptor Potential Vanilloid 4 (TRPV4) channel response to hypoosmotic stress, provides not only an important insight into the heart as an adaptive mechanosensitive organ in maintaining health but also its ability to modulate calcium handling in response to hypertensive stress and disease states. Under hypoosmotic conditions, cardiac myocytes undergo a transient positive inotropic effect (Pie), raising levels of intracellular calcium and increasing contractile force [2,3]. However, the exact mechanism that links changes in osmotic balance with a rise in intracellular calcium remains elusive. TRPV4, a nonselective cation channel, is widely expressed in the vascular smooth muscle and endothelium, and increased expression in models of hypertension may contribute to increased vasoconstriction and high blood pressure [4,5]. Here, the authors investigate the contribution of TRPV4 to hypotonic swelling-induced Pie in cardiomyocytes and mechanical stretch, providing an interesting insight into calcium mishandling in the spontaneously hypertensive rat (SHR). In healthy Wistar rats, hypotonic swelling induced a transient Pie, and this effect was shown to be independent of TRPV4 activity. However, in the SHR heart, TRPV4 expression was significantly increased, and blocking of the channel reversed hypotonic swelling-induced contractility and prevented cellular Ca2+ entry. Translationally, this study is critical in identifying a role for TRPV4 as an adaptive ion channel that responds to hypertensive stress and its role in cellular Ca2+ entry and therefore its ability to modulate the contractile response. This study, alongside others, provide support for the role of TRPV4 as a mechanosensitive Ca2+ channel, activated by the hypotonic environment, to regulate contractility in the healthy heart [6,7]. Interestingly, this study is the first to suggest a role for TRPV4 in the SHR. This effect could be a compensatory mechanism to ensure Ca2+ entry is not diminished in hypertension and contractility is not affected in this disease state. However, this compensatory mechanism could potentially worsen the hypertensive phenotype seen in the SHR, by promoting Ca2+ overload and as suggested by other studies, cardiac remodelling over time [8]. Further supporting this, other studies have shown that endothelial specific deletion of TRPV4 preserves cardiac function, cardiomyocyte structure and reduces cardiac fibrosis [9,10], suggesting this channel may be detrimental in worsening the effects of chronic hypertension. These findings lay the foundations for avenues of future work. Firstly, understanding the dependence of TRPV4 on other cellular mechanosensitive proteins may enable its therapeutic potential to be studied, and the ability to further elucidate the mechanism by which a hypertensive phenotype develops. Furthermore, modulating expression of TRPV4 may offer a new alternative therapy for preventing Ca2+ and restoring mechanical homeostasis lost in hypertension. Whilst this study provides strong evidence that TRPV4 contributes the stretch-induced Ca2+ entry in SHR hearts, most experiments were performed in isolated cardiomyocytes or papillary muscle strips. Further in-vivo experiments would enable channel functioning to be explored in a relevant physiological context and to understand downstream signalling pathways involved. Considering females have a differing remodelling pattern to males under hypertensive stress, taking into account sex-related differences would further aid in understanding the if TRPV4 channel acts in a sex-dependent manner when responding to mechano-osmotic stressors [11]. In conclusion, this excellent study aids our understanding of mechanosensitive Ca2+ regulation in hypertension and reinforces the importance of channels such as TRPV4 in the switch from a healthy compensatory contractile mechanism to chronic hypertension and potential heart failure. Targeting channels such as TRPV4 may be key preventing hypertension-induced cardiac dysfunction without compromising normal physiological mechanotransduction in healthy tissue. ACKNOWLEDGEMENTS H.M.W. is supported by British Heart Foundation grant FS/PhD/24/29467. S.N.S is supported by British Heart Foundation grant PG/22/11044. Sources of funding: British Heart Foundation nonclinical PhD studentship FS/PhD/24/29467, British Heart Foundation and Rosetrees Trust PG/22/11044. Conflicts of interest There are no conflicts of interest.