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Estrogen Modulates Endothelial and Neuronal Nitric Oxide Synthase Expression via an Estrogen Receptor ß-Dependent Mechanism in Hypothalamic Slice Cultures

Center for Neuroscience and Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada T6G 2H7

Address all correspondence and requests for reprints to: Dr. Teresa L. Krukoff, Center for Neuroscience and Department of Cell Biology, 5-31 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. E-mail: teresa.krukoff{at}ualberta.ca.

Although it is evident that estrogen has important physiological effects in the brain, the signaling mechanisms mediating these effects remain unclear. We recently showed that estrogen mediates attenuated blood pressure responses to psychological stress in ovariectomized female rats through brain nitric oxide (NO). An area likely to mediate these effects is the hypothalamic paraventricular nucleus (PVN), because here NO exerts inhibitory effects on autonomic output to the periphery. Because little is known about how estrogen acts on the NO system in the PVN, our aim was to study the effects of estrogen on the NO system in the PVN of hypothalamic slices cultures. We show that 17ß-estradiol (E2; 1 nM) increases endothelial NO synthase (eNOS) protein expression and decreases the numbers of neuronal NOS (nNOS)-positive neurons in the PVN after 8 and 24 h, respectively. Using the nonselective estrogen receptor (ER) antagonist, ICI 182,780 (10 nM), we determined that E2-induced changes in NOS expression in the PVN are ER dependent. Using the ERß agonist, genistein (0.1 µM), we determined that activation of ERß induces increased eNOS expression and a decreased number of nNOS-positive neurons. We used the selective ER agonist, propyl-pyrazole-triol (10 nM), and antagonist, methyl-piperidino-pyrazole (1 µM), to exclude the possibility that ER is involved in the E2-induced increase in eNOS and nNOS in the PVN. These results demonstrate that E2 induces changes in NOS expression in the PVN and that these effects are ERß dependent.

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