The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability

Abstract

Objective: We investigated the effect of estrogen replacement on the structure and function of penetrating brain arterioles (PA) and blood-brain barrier (BBB) permeability.

Materials and methods: Female ovariectomized Sprague-Dawley rats were replaced with estradiol (E(2)) and estriol (E(3)) (OVX + E; N=13) and compared to ovariectomized animals without replacement (OVX; N=14) and intact controls (CTL, proestrous; N=13). Passive and active diameters, percent tone, and passive distensibility of pressurized PA were compared. In addition, BBB permeability to Lucifer Yellow, a marker of transcellular transport, was compared in cerebral arteries.

Results: Ovariectomy increased myogenic tone in PA, compared to CTL, that was not ameliorated by estrogen treatment. Percent tone at 75 mmHg for CTL vs. OVX and OVX + E was 44+/-3% vs. 51+/-1% and 54+/-3% (P<0.01 vs. CTL for both). No differences were found in passive diameters or distensibility between the groups. BBB permeability increased 500% in OVX vs. CTL animals; however, estrogen replacement restored barrier properties: flux of Lucifer Yellow for CTL, OVX, and OVX + E was (ng/mL): 3.4+/-1.2, 20.2+/-5.3 (P<0.01 vs. CTL), and 6.15+/-1.2 (n.s.).

Conclusions: These results suggest that estrogen replacement may not be beneficial for small-vessel disease in the brain, but may limit BBB disruption and edema under conditions that cause it.

Figure 1

Active lumen diameter vs. intravascular pressure for parenchymal arterioles (PA) from control (CTL), ovariectomized (OVX) and estrogen treated ovariectomized (OVX+E) Sprague-Dawley rats. No significant differences in active lumen diameters were found between the groups. Forced dilation occurred at 150 mm Hg for all groups.

Figure 2

Percent myogenic tone of parenchymal arterioles (PA) from control (CTL), ovariectomized (OVX) and estrogen treated ovariectomized (OVX+E) Sprague-Dawley rats at pressure from 50-200 mm Hg. OVX animals had increased tone compared to CTL animals, that was not restored by estrogen replacement. *P < 0.05 versus CTL, ** P < 0.01 versus CTL

Figure 3

Passive lumen diameter vs. pressure of parenchymal arterioles (PA) from control (CTL), ovariectomized (OVX) and estrogen replaced ovariectomized (OVX+E) Sprague-Dawley rats. No significant differences were found between groups.

Figure 4

Percent passive distensibility vs. pressure of parenchymal arterioles (PA) from control (CTL), ovariectomized (OVX) and estrogen replaced ovariectomized (OVX+E) Sprague-Dawley rats. No significant differences were found between groups.

Figure 5

Blood-brain barrier permeability to Lucifer Yellow (LY). A, Graph showing permeability at each pressure for posterior cerebral arteries (PCA) from control (CTL), ovariectomized (OVX) and estrogen replaced ovariectomized (OVX+E) Sprague-Dawley rats. B, Flux of LY calculated from the average slope (m) of the regression lines for permeability vs. intravascular pressure. OVX animals had a significantly higher permeability to LY compared to CTL animals, while OVX+E animals showed permeability similar to CTL animals. ***P < 0.001 versus CTL; **P < 0.01 versus CTL; *P < 0.05 versus CTL; ⇞⇞ P<0.01 vs. OVX+E; ⇞ P<0.05 vs. OVX+E.