Abstract: Objective To evaluate the effect of physiological dose 17-β-estrodiol (E2) replacement therapy on vascular dementia
caused by cerebral chronic hypoperfusion. Methods The rats with bilateral common carotid artery occlusion (BCCAO)
received E2 treatment starting from 3 days or 3 months after the operation. IgG leakage into the brain parenchyma and the
changes of microvascular ultrastructure following BCCAO were examined using immunohistochemistry and electron
microscopy, respectively; Western blotting was used to detect the expression of vascular endothelial growth factor (VEGF)
protein. Results Compared with the sham-operated groups, the rats at 3 days and 3 months after BCCAO showed extensive
vascular damages surrounded by IgG immunoreactivity in both the cortical and hippocampal CA1 regions. Stronger IgG
immunoreactivity in the hippocampal CA1 region was observed at 3 days after BCCAO than at 3 months, but no significant
IgG leakage was found in rats with continuous E2 treatment. Electron microscopy revealed severe edema around the blood
vessels, mild vascular dilation, and endothelial cell damages at both 3 days and 3 months after BCCAO. E2 treatment
markedly reduced the microvascular ultrastructural damages. Western blot analysis showed a significant increase in VEGF
expression in the CA1 region at 6 h and 1 day after BCCAO followed by an obvious reduction till reaching the lowest level at 3
days; VEGF expression remained low even at 3 months after BCCAO and was significantly increased by E2 treatment.
Conclusions Vascular structural damage occurs early after BCCAO and can last for 3 months. E2 replacement therapy at
physiological doses can reduce the incidence of BCCAO-induced vascular dementia by up-regulating VEGF expression.