Differences in neurocardiovascular derangement between male and female chronic mild stress rat model: the role for renal afferent sympathetic nerves

Chronic psychological stress that leads to depression has been identified as an important driver of cardiovascular disease (CVD) in major epidemiological cohorts, such as the INTERHEART and INTERSTROKE studies. We recently showed in the CARDIA cohort that higher depression scores in women in their young adulthood were positively associated with vascular aging index 20 years later (b-weight 0.186, p = 0.015) while such was not found for men. Dysregulation of the hypothalamic-pituitary-adrenal axis and hyperactivity of the sympathetic nervous system contribute to the development and progression of CVD and can be initiated by depression and chronic stress. We previously showed that the activation of V1a and V1b receptors in the paraventricular nucleus by vasopressin in a rat model of chronic mild unpredictable stress (CMS) led to increased mean arterial pressure (MAP) and augmented renal sympathetic nerve activity (RSNA) in males. Here we set out to determine a) how CMS impacts central vessel stiffness in male and female rats and how it impacts cardiovascular derangement in female rats specifically, and b) the relative contribution of afferent vs. efferent renal sympathetic nerves to the sympathetic tone in CMS. We hypothesized that the renal afferent, rather than efferent, nerves are responsible for the rise in MAP and aortic stiffness in CMS males but not females (hormonally intact). We used the 4-week CMS exposure paradigm to induce depression in our rats, followed by a 4-week recovery period during which the stressors were fully removed. Aortic stiffness was assessed in vivo by measuring aortic PWV (aPWV) with Doppler ultrasound. While CMS causes an increase in MAP (142 ± 4 vs. 118 ± 4 mmHg in controls) and RSNA (11.9 ± 3.7 vs 4.5 ± 1.8 µV·s in controls) in male rats, it results in increased RSNA (21.1 ± 7.7 vs 6.8 ± 0.3 µV·s in controls) but not MAP in female rats. Furthermore, aPWV was higher in CMS males (761 ± 23 mm/s) compared to unstressed counterparts (594 ± 26 mm/s), and was reduced in the group of males that underwent the stress reduction period (568 ± 93 mm/s). On the contrary, CMS did not affect aPWV in females (517 ± 56 vs 554 ± 17 mm/s in controls). To investigate the relative contribution of efferent vs. afferent renal sympathetic fibers in increasing MAP in males, we completed either total renal denervation (TRDNx) or selective afferent renal nerve (ARDNx) ablation. After 4 weeks of CMS, MAP measured via telemetry was equally reduced in both TRDNx and ARDNX groups and was comparable to control sham-operated male rats. Our data suggest that the renal afferent, rather than efferent, nerves are responsible for the rise in MAP and aortic stiffness in CMS males, and that hormonally intact female CMS rats are protected from increases in MAP and aPWV. University Research Grant 2023-24, Wayne State University School of Medicine Start up funds at Wayne State University School of Medicine 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.