Stress-induced reduction in ACE2 activity and raised hypothalamic activation in aging female rats: novel insights into the origins of hypertension following menopause

Abstract

Introduction: The onset of menopause increases the development of cardiovascular diseases and hypertension. However, only a subpopulation of menopausal women develops these disorders. The origins of such distinct aging trajectories are unknown. Since stress has persistent and sex-specific effects on health, we hypothesized that early-life stress exacerbates the cardiovascular consequences of the loss of ovarian function in aging rats. Methodology: Neonatal maternal separation (NMS) is a clinically relevant model of early-life stress. Following birth, rats were either raised under standard conditions (CTRL) or subjected to NMS (3h/day from postnatal days 3 to 12). When the females reached 60 weeks (old age), we measured arterial blood pressure by the “tail-cuff” method. We then measured the activity of the angiotensin-converting enzyme (ACE) and its homolog ACE 2 in serum, two key enzymes involved in the homeostasis of the renin-angiotensin system (RAS). Finally, we compared the expression of FosB, a transcription factor indicating neuronal activity, in the paraventricular nucleus of the hypothalamus (PVN); this structure is involved in the development and maintenance of hypertension and regulation of stress responses. The PVN contains two major anatomical structures: magnocellular (vasopressin secretion) and parvocellular (neuroendocrine-related functional and central autonomic control). Results: The mean arterial blood pressure (MAP) of NMS females was 12% higher than CTRL but the heart rate was 9% lower. Interestingly, in our previous studies, this stress effect was not observed in young adults (8 weeks old). The catalyzed activity of ACE was similar between groups, but ACE2 activity was 60% lower in NMS. The number of neurons expressing FosB was 55% higher in the magnocellular region of the PVN in NMS females. Finally, we observed a strong negative correlation between ACE2 activity and MAP (r2= -0.71, p=0.002). Conclusions: Unlike CTRL, aged NMS females showed an increased risk of hypertension. The lower activity of ACE2 may lead to an accumulation of Angiotensin II, which stimulates the release of vasopressin. Vasopressin, in turn, inhibits the secretion of renin. Increased renin predisposes individuals to develop hypertension. The increased magnocellular activation of PVN indicated that the vasopressin and the RAS may be interacting and contributing increased MAP. Therefore, we conclude that loss of ovarian function reveals the effects of early-life stress on cardiovascular homeostasis in females. DAM is supported by the FRQ-S (268346) and the “Programme de complément de bourse” from RSRQ (2021-22). This research is supported by the Canadian Institutes of Health Research (RK). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.