Neuroendocrine regulatory effects of sex hormones on salt sensitivity of blood pressure

We read with great interest the Review by S. K. Masenga 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)¹. The authors summarized the interactions between sex hormones, the renin–angiotensin–aldosterone system and the epithelial Na⁺ channel in the development of salt-sensitive hypertension¹. Oestrogen is protective against salt-sensitive hypertension in women (especially premenopausal women) through its activation of the mitogen-activated protein kinase signalling pathway and downstream protein phosphorylation to increase nitric oxide production in endothelial cells, while inhibiting oxidative stress and inflammation by reducing the synthesis and activity of NADPH oxidases and suppressing nuclear factor of activated T cells (NFAT) transcription factors¹. The Review further mentioned the potential role of sex-specific differences in renin–angiotensin–aldosterone system activation and expression of the epithelial Na⁺ channel in salt-sensitive hypertension¹. We believe that some other crucial information should be taken into account to fully understand the complex mechanisms regulating the salt sensitivity of blood pressure based on sex hormones.

First, the Review mentioned that nitric oxide production in female and male rats was regulated by transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential canonical 3 (TRPC3), respectively¹. Although some studies have shown that activation of TRPV4-dependent Ca²⁺ influx has an important role in endothelium-dependent vasodilatation, other studies have found that TRPV4 mediates vasoconstriction and high-salt-induced hypertension^2,3. In addition, TRPV4 is also involved in the perception of variation in blood osmotic pressure by osmotic pressure receptor neurons in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and the regulation of antidiuretic hormone (also known as vasopressin)⁴. Trpv4-knockout mice have impaired osmoregulation under hypertonic stress, leading to elevated systemic osmotic pressure⁵. Therefore, further research on the effects of TRPV4 on the vascular endothelium and blood pressure and the underlying mechanisms is essential.