Redistribution of NMDA Receptors in Estrogen Receptor β-Containing Paraventricular Hypothalamic Neurons Following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure.

Hypertension in male and aging female rodents is associated with glutamate-dependent plasticity in the hypothalamus, but existing models have failed to capture distinct transitional menopausal phases that could have a significant impact on the synaptic plasticity and emergent hypertension. In rodents, accelerated ovarian failure (AOF) induced by systemic injection of 4-vinylcyclohexane diepoxide mimics the estrogen fluctuations seen in human menopause including the perimenopause transition (peri-AOF) and postmenopause (post-AOF). Thus, we used the mouse AOF model to determine the impact of slow-pressor angiotensin II (Ang ll) administration on blood pressure and on the subcellular distribution of obligatory N-methyl-D-aspartate (NMDA) receptor GIuN1 subunits in the paraventricular hypothalamic nu-cleus (PVN), a key estrogen-responsive cardiovascular regulatory area. Estrogen-sensitive neuronal profiles were identified in mice expressing enhanced green fluorescent protein under the promoter for estrogen receptor (ER) beta, a major ER in the PVN. Slow-pressor Angll increased arterial blood pressure in mice at peri-and post-AOF time points. In control oil-injected (nonhypertensive) mice, Angll decreased the total number of GIuN1 in ERR-containing PVN dendrites. In contrast, Angll resulted in a reapportionment of GIuN1 from the cytoplasm to the plasma membrane of ER beta-containing PVN dendrites in peri-AOF mice. Moreover, in post-AOF mice, Angll increased total GIuN1, dendritic size and radical production in ERR-containing neurons. These results indicate that unique patterns of hypothalamic glutamate receptor plasticity and dendritic structure accompany the elevated blood pressure in peri-and post-AOF time points. Our findings suggest the possibility that distinct neurobiological processes are associated with the increased blood pressure during perimenopausal and postmenopausal periods.