Differing ionotropic glutamate receptor gene expression in paraventricular hypothalamic nucleus subregions following angiotensin II hypertension in male mice and female mice with advanced ovarian failure

Introduction: The increased susceptibility to hypertension at menopause is characterized by alterations in brain circuits that regulate cardiovascular homeostasis, however, the mechanisms underlying this association are not well understood. Recent evidence using an accelerated ovarian failure (AOF) model of menopause demonstrates that hypertension is critically dependent on ionotropic glutamate receptor signaling in the hypothalamic paraventricular nucleus (PVN), a brain area critical for blood pressure regulation. There are various glutamate receptors (i.e., NMDA, AMPA) and functionally diverse PVN subregions (i.e. endocrine, autonomic), yet regional gene expression patterns of specific receptors during hypertension in AOF mice is lacking. Methods: In situ hybridization was used to map gene expression of glutamate receptors in functionally distinct PVN subregions. Mice were infused with slow-pressor angiotensin II (AngII) at a late stage of AOF comparable to post-menopause and were compared to age-matched male mice. Group differences in gene expression were found in a manner that varied according to PVN subregion, gene, sex, and hypertension status. Results: Notable hypertension-related divergences in expression of AMPA or NMDA receptor genes important for neural plasticity were seen only in males and were found in mediocaudal PVN subregions that are known to project to brainstem and spinal regions implicated in autonomic processes (Gria1 and Grin2a, respectively) or the anterior pituitary region (Gria2). Conclusion: These findings demonstrate that altered expression of key ionotropic glutamate receptor genes is limited to regions critically involved in modulating sympathetic and parasympathetic activity as well as neuroendocrine processes in males only.