Dichotomy of Chronic Mild Stress effects on blood pressure and longitudinal measurements of renal sympathetic nerve activity: are females really protected?

Chronic psychological stress that leads to depression has been described as an important driver of cardiovascular disease (CVD). The rat model of chronic mild stress (CMS) recapitulates the behavioral aspects of human depression, and we also previously showed that 4 weeks of CMS recapitulates cardiovascular disturbances, including increased blood pressure (BP) and renal sympathetic nerve activity (RSNA), albeit in male rats only. Our previous data from the human CARDIA cohort showed that higher depression scores in women in their young adulthood were associated with higher vascular aging index two decades later (b-weight 0.186, p = 0.015). Previously published studies showed that the risk of cardiovascular morbidity and mortality is lower in premenopausal females compared to age-matched males, only to increase significantly and surpass that of the age-matched males after menopause. Which physiological parameters set the stage for the skyrocketing of CVD in females post-menopause is incompletely understood. Most of the evidence for men indicates that independent of systolic blood pressure (SBP), increased muscle sympathetic activity (MSNA) was associated with vascular stiffness, whereas in females the evidence is unclear pre- vs. post-menopause with some studies showing a correlation between increased vascular stiffness and increased MSNA burst frequency. Here we set out to determine for the first time the hemodynamic and renal sympathetic outcomes recorded continuously over 7 days in unanesthetized, freely moving female CMS rats. We hypothesized that even though BP remains the same after 4 weeks of CMS in hormonally intact female rats, RSNA and aortic pulse wave velocity (aPWV, an index of central vessel stiffness) both increase. We studied n = 11 Sprague Dawley female rats, aged 9-11 weeks. Baseline echocardiography was completed on day 0. After that, n = 6 rats were exposed to CMS paradigm for 4 weeks (CMS group), and n= 5 rats remained housed under normal conditions (control group). After 4 weeks, the rats were instrumented with Kaha dual BP and SNA telemeters and BP and RSNA were monitored for 7 days (i.e. day 29-35 post-CMS) continuously in freely moving rats, followed by final echocardiography. Data was analyzed with mixed-effects ANOVA accounting for the estrous cycle stage. There was no change in mean arterial pressure between CMS and controls on day 29 through day 35 (99 +/- 6 vs. 101 +/- 4 mmHg on day 29, respectively), SBP, diastolic BP, or heart rate. However, pulse pressure was higher in CMS on days 29 - 35 (53 +/- 1 vs. 47 +/- 2 mmHg on day 29, p < 0.05) and aPWV change was larger in CMS rats on day 29 (173.2 +/- 50.9 mm/s, p < 0.05) while it remained unchanged in the controls (-10.7 +/- 54.6 mm/s). RSNA burst characteristics revealed higher sympathetic activation in CMS rats compared to controls, that was sustained days 29-35, as evidenced by increased burst incidence (2.39 +/- 0.22 vs. 1.44 +/- 0.12 bursts/beat, p < 0.001), decreased burst width50 (18.5 +/- 2.3 vs. 24.4 +/- 1.4 ms, p < 0.001), and lower Tau (8.41 +/- 0.71 vs. 11.87 +/- 0.88 ms, p < 0.001). These results indicate that even though BP remains the same in females exposed to CMS, sustained increase in RSNA and the sympathetic input into other vascular beds may be responsible for increase in arterial stiffness. This raises an important translational point that in the absence of increase in BP in pre-menopausal females, further evaluation of the cardiovascular system may not be warranted, representing a missed opportunity for early intervention and prevention of CVD developing later in life. This work was supported by start-up funds to DK. This abstract was presented at the American Physiology Summit 2026 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.