Ovarian Hormone Deprivation Reduces Oxytocin Expression in Paraventricular Nucleus Preautonomic Neurons and Correlates with Baroreflex Impairment in Rats

Abstract

The prevalence of cardiovascular diseases including hypertension increases dramatically in women after menopause, however the mechanisms involved remain incompletely understood. Oxytocinergic (OTergic) neurons are largely present within the paraventricular nucleus of the hypothalamus (PVN). Several studies have shown that OTergic drive from PVN to brainstem increases baroreflex sensitivity and improves autonomic control of the circulation. Since preautonomic PVN neurons express different types of estrogen receptors, we hypothesize that ovarian hormone deprivation causes baroreflex impairment, autonomic imbalance and hypertension by negatively impacting OTergic drive and oxytocin levels in pre-autonomic neurons. Here, we assessed oxytocin gene and protein expression (qPCR and immunohistochemistry) within PVN subnuclei in sham-operated and ovariectomized Wistar rats. Conscious hemodynamic recordings were used to assess resting blood pressure and heart rate and the autonomic modulation of heart and vessels was estimated by power spectral analysis. We observed that the ovarian hormone deprivation in ovariectomized rats decreased baroreflex sensitivity, increased sympathetic and reduced vagal outflows to the heart and augmented the resting blood pressure. Of note, ovariectomized rats had reduced PVN oxytocin mRNA and protein expression in all pre-autonomic PVN subnuclei. Furthermore, reduced PVN oxytocin protein levels were positively correlated with decreased baroreflex sensitivity and negatively correlated with increased LF/HF ratio. These findings suggest that reduced oxytocin expression in OTergic neurons of the PVN contributes to the baroreflex dysfunction and autonomic dysregulation observed with ovarian hormone deprivation.

Influence of testosterone on mean arterial pressure: A physiological study in male and female normotensive WKY and hypertensive SHR rats

“…The findings in male WKY and SHR rats in which orchidectomy had also caused a decrease in blood pressure have further strengthened the view that testosterone is involved in increasing the blood pressure, a finding similar to that found by others (23). There were conflicting reports with regard to the effect of ovariectomy on MAP (9,35,42). Ovariectomy has been reported not to cause changes in blood pressure of wild-type mice.…”

“…The effects of sex-steroid hormones on blood pressure in females are far more complex and less well understood as compared with the effects of these hormones on blood pressure in males. Female blood pressure was found to be influenced by estrogen (9,18,46).…”

Plasma Oxytocin Concentration in Pre- and Postmenopausal Women: Its Relationship with Obesity, Body Composition and Metabolic Variables

“…A mechanistic interplay linking oxytocin, hypoestrogenism, and adiposity has been suggested in animal studies showing that: i) ovarian hormone deprivation plays a critical role on oxytocin activity and its expression in the hypothalamic nuclei involved in the control of food intake [25]; ii) hypothalamic and circulating oxytocin are associated with fasting-feeding cycles [32]; iii) weight gain accompanying ovariectomy is blunted by exogenous oxytocin administration [33]; iv) gene knockout of oxytocin and its receptor promotes obesity [15]; v) carriers of mutations related to Sim1 haplo-insufficiency and MAGED1 deficiency harbor low hypothalamic expression of oxytocin and obesity [34,35]. Complimentarily, oxytocin levels have been found decreased in most but not all animal models of obesity and T2DM, including diet-induced-obesity (DIO) and carriers of leptin deficiency [16,36,37].…”

“…Studies in rodents have consistently demonstrated that estrogen deprivation decreases plasma oxytocin levels [25]. In humans, cross-sectional analysis found that oxytocin circulates at lower levels in amenorrheic athlete women than in non-amenorrheic control women [26].…”

Associations of oxytocin with metabolic parameters in obese women of childbearing age

“…The grey area represents the 95% CI of the coefficients, the black curve represents the estimated coefficients, and the dotted line represents some studies suggested that ovarian function is slightly lower in obese women than in healthy control subjects of young reproductive age, although ovarian reserve parameters are in normal reference range [18,19]. In addition, some studies also revealed that lacking oestradiol can blunt oxytocin expression, decreasing circulation levels of oxytocin, and inhibiting signalling in pre-autonomic areas of the hypothalamus [20].…”