Reply to ‘Neuroendocrine regulatory effects of sex hormones on salt sensitivity of blood pressure’

Abstract

We appreciate the opportunity to reply to the points raised by M. Zhou et al. (Neuroendocrine regulatory effects of sex hormones on salt sensitivity of blood pressure. Nat. Rev. Cardiol. https://doi.org/10.1338/10.1038/s41569-025-01175-6 2025)¹ on our Review (Masenga, S. K. et al. Salt sensitivity of blood pressure: mechanisms and sex-specific differences. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-025-01135-0 2025)².

Transient receptor potential vanilloid 4 (TRPV4) is a Ca²⁺-permeable channel expressed in endothelium and neurons. Evidence indicates that endothelial TRPV4 activation causes vasodilatation by increasing intracellular Ca²⁺ concentration, which triggers nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor pathways³. However, under certain conditions (such as strong agonism or in specific vascular beds), TRPV4 activation can paradoxically evoke vasoconstriction³. Therefore, reports of a ‘dual’ role are context dependent: mild TRPV4 activation produces net vasodilatation, whereas very high TRPV4 activity or TRPV4 activation in specific vessels can cause vasoconstriction. Importantly, TRPV4 activation (with 4α-phorbol 12,13-didecanoate (4α-PDD)) has been shown to acutely lower blood pressure in rats, and a high-salt diet augments this hypotensive effect⁴. In the latter study, rats receiving a high-salt diet expressed more TRPV4 and had a larger drop in blood pressure in response to TRPV4 agonism, suggesting that TRPV4 provides a compensatory vasodilatory response to salt loading⁴.