The effect of postmenopausal
estrogen replacement therapy (ERT) on the risk or severity of
cerebrovascular disorders is as yet unclear, and the evidence for flow preservation being a mechanism of
estrogen neuroprotection remains elusive. The authors examined whether
estrogen-mediated flow-preserving neuroprotective mechanisms, if any, may involve its angiogenic action. This study was conducted using middle-aged (44 weeks) female rats because of the importance of aging in
cerebrovascular disease in women. Middle-aged female rats were subjected to
sham operation,
ovariectomy, or
ovariectomy with ERT. The anatomic cerebral capillary morphology showed a significant reduction in the total capillary density in the frontal cortex after
ovariectomy. This was associated with marked decreases in
protein and gene expression of
vascular endothelial growth factor and its angiogenic receptors in cerebral vessels, as demonstrated by immunohistochemistry and hybridization. The expression levels of both
estrogen receptor (ER) subtypes,
ERalpha and
ERbeta, in cerebral vessels were significantly reduced after
ovariectomy, but
ERbeta was more dramatically downregulated as assessed by the
ERbeta/
ERalpha ratio. These
ovariectomy-induced changes were completely prevented by ERT.
Vascular endothelial growth factor appears to be a critical regulatory molecule for physiologic cerebral angiogenesis in middle-aged female rats and may play an important role in the flow-preserving neuroprotective action of
estrogen through its angiogenic and antiapoptotic properties.