Cerebral Blood Flow Changes

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A lower incidence of stroke and vascular events in premenopausal women has been well documented, as has an increase in these events in women after menopause.7 Although indirect effects of estrogens on cardiac risk factors — such as estrogen's lipid-lowering effect — are partially responsible, direct effects of estrogen on the blood vessel wall may play an important role. These direct vascular effects of estrogens may also underlie much of the hormone's neuroprotection after brain injury.

A number of published studies have shown an effect of estrogen on microvascu-lar vasomotor tone and production of vasoactive substances. Mendelsohn and Karas12 describe four mechanisms by which estrogen can produce rapid vasomotor effects. These include estrogen-induced, endothelium-derived relaxing factor (EDRF) release, estrogen antagonism of vasoconstrictor responses to endothelin, direct hyperpolarizing effects of estrogen on resting vascular smooth muscle, and rapid estrogen antagonism of vascular smooth-muscle calcium channels. Estrogen may also upregulate genes for rate-limiting enzymes in the biosynthesis of two important vasodilators, prostacyclin (PGI2)40-43 and EDRF,44 the latter now identified as nitric oxide (NO*). All of these actions would serve to counteract vasoconstriction or cause vasodilation.

Such effects on the microvasculature by estrogen could become important because of the hypoperfusion that often immediately follows stroke. A reduction in adequate blood supply to the brain is among the secondary intracranial events that result from the brain's physiologic response to severe traumatic injury. If sufficient blood flow to the brain is not maintained, ischemic damage to brain tissue will rapidly follow. An improvement in blood flow by estrogen would serve to reduce the extent of secondary damage that results.

Several studies provide evidence for such a role of estrogen after acute brain ischemia. Hurn et al.,45 for example, examined postischemic cerebral blood flow (CBF) in male, female, and estrogen-treated female rabbits subjected to a brief episode of four-vessel occlusion-induced forebrain ischemia followed by 3 hours of reperfusion. They found that while baseline blood flow did not differ among the groups, postreperfusion hyperemia was greater in females than in males after a four-vessel occlusion and 3-hour reperfusion. Chronic 170-estradiol treatment of females caused higher CBF during ischemia and reduced postreperfusion hyperemia in several brain regions compared to non-treated females.

In another study by the same group, the effect of ovariectomy on the gender difference in postischemic CBF was examined.18 Age-matched male, female, and ovariectomized female rats from two strains — normotensive Wistar and stroke-prone spontaneously hypertensive rats — were subjected to 2 hours of intraluminal MCAO, followed by 22 hours of reperfusion. CBF was monitored by laser-Doppler flowmetry. Female rats of both strains maintained a higher relative flow during ischemia compared to males and ovariectomized females. Volume of tissue with end-ischemic CBF <10 ml/100 g/min was smaller in females compared to males (but not different from ovariectomized females). Female rats also sustained smaller cortical and striatal infarcts after occlusion compared to age-matched males of both strains. Ovariectomy did not affect the volume of severely ischemic tissue. However, in a later study,46 the same group found that 170-estradiol treatment of ovariectomized rats did not improve CBF during ischemia, although it did result in infarct volume reduction. These combined findings support a flow-preserving effect of endogenous estrogen during cerebral ischemia but suggest that other mechanisms are involved in estrogen's neuroprotection as well.

Further evidence for estrogen's CBF-preserving effect has been provided by Stubley et al.,33 who compared post-MCAO CBF in ovariectomized rats with that of ovariectomized rats implanted with 17a-estradiol pellets. During reperfusion, non-treated ovariectomized rats showed an average recovery in CBF of approximately 50% of the pre-MCAO levels, where it remained for 24 hours. The CBF of estrogen-treated ovariectomized rats, on the other hand, promptly returned to pre-MCAO levels during reperfusion. The observed differences in CBF were associated with corresponding differences in infarct size.

Pelligrino et al.,26 reported that ovariectomy resulted in an exacerbation of the CBF drop experienced by intact female rats subjected to 30 minutes of forebrain ischemia (right common carotid-artery occlusion + hemorrhagic hypotension to 30 mmHg). This effect was reversed with low-dose chronic estrogen treatment.

figure 1.2 CBF following closed head injury in (A) intact and ovariectomized female rats treated with estrogen or vehicle and (B) male rats treated with estrogen or the vehicle. Asterisk (*) indicates significant difference between the groups at that time point at the p < 0.05 confidence level.

Ovariectomized females injected with 0.1 mg/kg of 17^-estradiol showed CBF recovery equivalent to normal females.

In a recent study of blood flow change after traumatic brain injury, Roof and Hall,47 using laser-Doppler flowmetry, demonstrated better recovery of CBF after impact-acceleration closed-head injury in female rats than in males. Ovariectomy partially eliminated the sex difference. Daily injections of 17^-estradiol for two weeks prior to injury resulted in improved postinjury CBF recovery in both males and females, as shown in Figure 1.2.

1.5.2 Vascular Nitric Oxide Formation

The results of many of the studies described above suggest that estrogen provides neuroprotection after ischemic injury, at least in some instances, by improving CBF. Hypoperfusion after brain injury can result from a combination of several factors, including hypotension, increased intracranial pressure, damage to the microvascula-ture, or loss of microvascular autoregulation. Microvascular autoregulation is a protective mechanism by which CBF and capillary perfusion pressure are kept relatively constant during changes in systemic blood pressure.48

One component of autoregulation is the myogenic response, which is the constriction or dilation of vascular smooth-muscle cells in response to increases or decreases in transmural pressure. An important modulator of the myogenic response is EDRF or nitric oxide (NO^). Interestingly, the myogenic tone of rat cerebral arteries has been shown to differ between males and females; and this difference appears to result from estrogen enhancement of NO^ production.44, 49-51 It has been shown that the vascular endothelium of female animals and humans produces more NO^ than that of males; that ovariectomy reduces basal NO^ levels; and that estrogen treatment of ovariectomized animals and postmenopausal women increases NO^ generation.52 Estrogen has been linked to increased expression and activity of both of the Ca2+-de-pendent isoforms of NO^ synthase (NOS), the endothelial isoform (eNOS), and neuronal isoform (nNOS). Although most of the evidence linking estrogen to increased NOS expression and activity comes from studies of peripheral tissue, there is evidence that the same occurs in the brain.26,27,53,54 Thus, it may be that the NO^-stimulat-ing effect of estrogen is a key mechanism underlying gender differences in blood flow change after ischemic injury.

One group recently directly addressed this possibility. Pelligrino et al.55,56 examined whether NOS activity is affected by ovariectomy and estrogen replacement and whether NOS-derived NO^ supports vasodilation during ischemia. They measured both CBF changes and NOS levels after transient forebrain ischemia in intact, ovariectomized, and 17P-estradiol-treated ovariectomized female rats and found a direct correspondence between the two measures. Ovariectomized females showed greater reductions in CBF than intact females. Estrogen treatment eliminated the difference. Likewise, NOS levels in brain tissue from the ovariectomized females were lower than from intact females. This difference was eliminated by estrogen treatment. These findings support the hypothesis that estrogen improves postinjury blood flow recovery by enhancing NOS expression.

Others have suggested that estrogen increases NO^ in the absence of changes in endothelial NO^ synthase gene expression.57,58 Barbacanne et al.58 found that exposure of bovine aortic endothelial cells to physiological doses of estrogens did not alter NOS gene expression, but rather induced an antioxidant effect (vide infra) that enhanced the biological activity of NO\ They also reported that in vivo estra-diol treatment decreased lucigenin-enhanced chemiluminescence of thoracic aorta from ovariectomized rats, demonstrating an estrogen-related decrease in O2- production. Since O2- is known to react with NO^ to form peroxynitrite, with O2- as the rate-limiting factor, decreased O2- results in more available NO\ This estrogen-induced increase in NO^ availability would then lead to vascular relaxation and increased blood flow.

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