Endothelial cell derived endothelin‐1 (ET‐1) regulates skin Na + storage: evidence for sex differences

Abstract

The skin stores sodium in response to chronic high salt intake providing a buffer for extracellular fluid volume through macrophage recruitment and lymph hyperplasia. ET-1 is increased in response to high salt intake and promotes pro-inflammatory and hyperplastic effects, although its role in skin Na+ storage is unknown. Therefore, the current study was designed to determine if vascular endothelial derived ET-1 is important to the skin buffering capacity and if sex differences exist in this response. After 2 weeks of either low (LS, .02%) or high (HS, 4%) NaCl diet, floxed control mice had a slight, but not statistically significant increase in skin Na+ concentration. Na+ content was similar in both males and females. This response was significantly exacerbated in VEET KO mice. Furthermore, tissue ET-1 peptide levels were significantly higher in response to HS in the ear, a highly vascularized skin tissue, of male floxed mice (85.9±0.9 ng/mg LS vs. 106.4± 6.8 ng/mg HS, p<0.05). Male VEET KO mice had significantly lower ET-1 in the ear compared to floxed controls with no difference between LS and HS (76.4±5.7 ng/mg LS vs. 65.7±7.9 ng/mg). In contrast, female mice have elevated ET-1 in the ear compared to males. Both floxed and VEET KO female mice have a similar increase in ear ET-1 in response to HS (floxed; LS vs. HS respectively, 113±13 vs. 141±23 ng/mg; VEET KO; LS vs. HS respectively, 112.0±16.2 LS vs. 156.3±24.1 ng/mg). These data support the hypothesis that vascular endothelial derived ET-1 plays a critical role in mediating skin storage of Na+ in response to a high salt intake. We also suggest that female mice have another source of ET-1 within the skin interstitium that may contribute to a greater ability to store and clear Na+ in the skin.