Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor β-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent

J Comp Neurol. 2014 Sep 1;522(13):3075-90. doi: 10.1002/cne.23569.


The incidence of hypertension increases after menopause. Similar to humans, "slow-pressor" doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased postsynaptic N-methyl-D-aspartate (NMDA) receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors β (ERβs) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2-month-old males and 18-month-old females, but not in 2-month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2-month-old females than in 2-month-old males or 18-month-old females. After AngII infusion, NR1-SIG density was decreased in 2-month-old females, but increased in 2-month-old males and 18-month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension.

Keywords: cardiovascular; estrogens; hypertension; sex differences.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / physiology*
  • Angiotensin II / administration & dosage*
  • Animals
  • Blood Pressure / drug effects
  • Dendrites / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Estrous Cycle / metabolism
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Paraventricular Hypothalamic Nucleus / cytology*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sex Factors
  • Stilbamidines / metabolism
  • Time Factors


  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Estrogen Receptor beta
  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Stilbamidines
  • Angiotensin II
  • Green Fluorescent Proteins