Female Dahl SS rats are more susceptible to increases in blood pressure on a high-fat, high-salt diet than males, is it Estrogen?

Hypertension affects over 1 billion people worldwide, and ~45% of women over the age of 18 are hypertensive. Interestingly, women are more likely to develop cardiovascular disease and hypertension due to obesity and salt intake than men. Historically, females have been considered protected from hypertension. However, our previous studies have shown that high-fat (HF) loading leads to greater increases in blood pressure (BP) on a HF/high-salt (HS) diet in females compared to males. These increases in BP in females are independent of body weight, adiposity, and renal function. The current study aims to test the hypothesis that enhanced susceptibility of females to a Western diet (HF/HS) is associated with impaired estradiol (E2)/estrogen receptor (ER) signaling. To test this hypothesis, 7-wk-old male and female Dahl rats were implanted with telemetry devices to continuously measure mean arterial BP (n=4-7/group). After a one-week recovery period, baseline BP was recorded for two weeks. Rats were then randomized to the following groups: 1) normal-fat/normal-salt diet (NF/NS, 7.2% calories from lard, 0.4% NaCl, Bio-Serv) throughout the study, 2) normal-fat diet (NFD) from 10-12 weeks of age, following by a NF/HS (4% NaCl, Bio-Serv) from 12-16 wks of age, or 3) HF diet (60% kcal from lard; Bio-Serv) from 10-12 wks of age, followed by a HF/HS diet (60% kcal from lard, 4% salt; Bio-Serv) from 12-16 wks of age. Baseline BP values were comparable between males (119±2 mmHg) and females (122±3 mmHg; NS). BP increased in both males and females during the 6 wks of NF/NS, but BPs remained comparable between the sexes (males: 133±2, females: 132±2; p=0.81). The NF/HS resulted in greater increases in BP than the control diet (males: 160±8 mmHg, females: 151±3 mmHg), and increases were similar in males and females (P diet <0.0001, P sex =28, P int =0.39). Interestingly, the Western diet, HF/HS, also increased BP in both sexes (males: 154±4 mmHg, females: 174±8 mmHg), but females exhibited a greater increase in BP than males vs. rats on the control diet (P diet <0.0001, P sex =0.071, P int =0.049). Plasma estradiol (E2) and testosterone (T) levels were measured using mass spectrometry. Compared to rats on the control diet (3.8±0.3 pg/mL), E2 was decreased in females fed HF/HS (0.77±0.1 pg/mL) but unchanged by HS (2.64±0.4 pg/mL; P=0.07, One-way ANOVA). E2 levels were undetectable in males. HF/HS increased T levels in females vs. controls (38.3±0.2 pg/mL vs. 10.5±0.3 pg/mL) with no change with HS (9.2±0.3 pg/mL; p=0.04, One-way ANOVA). T levels were not altered by diet in males (P=0.17, One-way ANOVA). As a result, there was a significant increase in the T to E2 ratio in the females fed HF/HS. Based on the importance of hormones in the control of BP, our findings underscore the need to better understand the impact of hormones in hypertension. Further studies are being conducted to understand the mechanism by which sex hormones influence blood pressure. NIHU54HL169191 and 5R01DK134695 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.