Chronic Estrogen Treatment Increases Levels of Endothelial Nitric Oxide Synthase Protein in Rat Cerebral Microvessels Editorial Comment (original) (raw)
Related papers
2010
Background and Purpose-A number of studies indicate that the female gonadal hormone, estrogen, confers protection against cerebrovascular disorders such as stroke. One postulated mechanism for these effects of estrogen is an action on the enzyme endothelial nitric oxide synthase (eNOS), which produces the vasodilatory molecule NO. We have investigated the hypothesis that estrogen increases expression of eNOS in cerebral microvessels of male and female rats. Methods-We measured levels of eNOS protein by Western blot in cerebral microvessels isolated from 7 groups of animals: females, ovariectomized females, ovariectomized females treated with estrogen, males, castrated males, castrated males treated with estrogen, and castrated males treated with testosterone. Results-Ovariectomized female rats treated with estrogen had 17.4-fold greater levels of eNOS protein in cerebral microvessels than ovariectomized females, and intact females had 16.6-fold greater levels than ovariectomized females (PϽ0.01). In intact females, cerebral microvessel eNOS protein levels were 9.2-fold higher than those of intact males (PϽ0.05). Levels of eNOS protein in castrated males, castrated males treated with testosterone, and males were not different from each other. Estrogen treatment of castrated animals resulted in an 18.8-fold increase in cerebral microvessel eNOS protein (PϽ0.05).
Journal of Applied Physiology, 2001
Duckles. Selected Contribution: Cerebrovascular NOS and cyclooxygenase are unaffected by estrogen in mice lacking estrogen receptor-␣. J Appl Physiol 91: 2391-2399, 2001.-Estrogen alters reactivity of cerebral arteries by modifying production of endothelium-dependent vasodilators. Estrogen receptors (ER) are thought to be involved, but the responsible ER subtype is unknown. ER-␣ knockout (␣ERKO) mice were used to test whether estrogen acts via ER-␣. Mice were ovariectomized, with or without estrogen replacement, and cerebral blood vessels were isolated 1 mo later. Estrogen increased levels of endothelial nitric oxide synthase and cyclooxygenase-1 in vessels from wild-type mice but was ineffective in ␣ERKO mice. Endothelium-denuded middle cerebral artery segments from all animals constricted when pressurized. In denuded arteries from ␣ERKO but not wild-type mice, estrogen treatment enhanced constriction. In endothelium-intact, pressurized arteries from wild-type estrogen-treated mice, diameters were larger compared with arteries from untreated wild-type mice. In addition, contractile responses to indomethacin were greater in arteries from wild-type estrogen-treated mice compared with arteries from untreated wild-type mice. In contrast, estrogen treatment of ␣ERKO mice had no effect on diameter or indomethacin responses of endothelium-intact arteries. Thus ER-␣ regulation of endothelial nitric oxide synthase and cyclooxygenase-1 pathways appears to contribute to effects of estrogen on cerebral artery reactivity. cerebral circulation; estrogen receptor-␣ knockout mice; nitric oxide synthase; gonadal steroids; ovariectomy
Beneficial Effects of Estrogen in a Mouse Model of Cerebrovascular Insufficiency
PLoS ONE, 2009
Background: The M 5 muscarinic acetylcholine receptor is known to play a crucial role in mediating acetylcholine dependent dilation of cerebral blood vessels. Previously, we reported that male M 5 muscarinic acetylcholine knockout mice (M5R 2/2 mice) suffer from a constitutive constriction of cerebral arteries, reduced cerebral blood flow, dendritic atrophy, and shortterm memory loss, without necrosis and/or inflammation in the brain.
Effect of estrogen therapy on cerebral arteries during stroke in female rats
Menopause, 2005
Objective: To investigate the effect of estrogen therapy on the structural and functional properties of the middle cerebral artery during ischemia and reperfusion. Design: Ovariectomized (OVX; n = 8) and ovariectomized with estrogen therapy (OVX+EST; n = 8) female Sprague-Dawley rats were exposed to 1 hour of ischemia using a model of temporary focal ischemia of the middle cerebral artery with 24 hours of reperfusion and compared to sham controls (CTL; n = 8). After occlusion and reperfusion, right middle cerebral arteries were removed from the brain and mounted on glass cannulas in a chamber that allowed for control over transmural pressure and measurement of lumen diameter. Lumen diameter was measured in response to increased transmural pressure (myogenic tone) as well as response to nitro-L-arginine, serotonin, and nifedipine. Cerebrovascular reactivity was compared to other stroke outcome measures, including infarct volume (%) and neurologic deficit. Results: Serum estrogen was increased in OVX+EST rats (60.5 6 18.2 pg/mL) compared to OVX (0.2 6 0.2 pg/mL P , 0.05 vs OVX+EST) and CTL animals (1.3 6 1.0 pg/mL P. 0.05 vs OVX). OVX showed significantly less myogenic tone at 75 mm Hg (13.8 6 3.6%, P , 0.05 vs CTL) than CTL (29.8 6 4.7%) that was partially restored by estrogen therapy (21.2 6 4.5;
Journal of Cerebral Blood Flow and Metabolism, 2000
Recently the authors have shown that female stroke-prone spontaneously hypertensive rats (SHRSPs) in pro estrus (high endogenous estrogen), sustain more than 20% smaller infarcts after middle cerebral artery occlusion (MCAO) compared with SHRSPs in metestrus (low endogenous estro gen). Because estrogen has vasodilator properties, the authors investigated whether the estrous state int1uences cerebral blood flow (CBF) after MCAO. CBF was measured 2.5 hours after a distal MCAO by e 4Cjiodo-antipyrine autoradiography in con scious SHRSPs either in metestrus or in proestrus. There were no significant differences in CBF when analyzed either at pre determined anatomic regions or by cumulative distribution
Estrogens as Protectants of the Neurovascular Unit Against Ischemic Stroke
Current Drug Target -CNS & Neurological Disorders, 2005
Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke.
Stroke in Estrogen Receptor- -Deficient Mice Editorial Comment
Stroke, 2000
Background and Purpose-Recent evidence suggests that endogenous estrogens or hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation during ischemic stress as well as direct preservation of neuronal viability. We hypothesized that if the intracellular estrogen receptor subtype-␣ (ER␣) is important to estrogen's signaling in the ischemic brain, then ER␣-deficient (knockout) (ER␣KO) female mice would sustain exaggerated cerebral infarction damage after middle cerebral artery occlusion. Methods-The histopathology of cresyl violet-stained tissues was evaluated after reversible middle cerebral artery occlusion (2 hours, followed by 22 hours of reperfusion) in ER␣KO transgenic and wild-type (WT) mice (C57BL/6J background strain). End-ischemic cerebral blood flow mapping was obtained from additional female murine cohorts by using [ 14 C]iodoantipyrine autoradiography. Results-Total hemispheric tissue damage was not altered by ER␣ deficiency in female mice: 51.9Ϯ10.6 mm 3 in ER␣KO versus 60.5Ϯ5.0 mm 3 in WT. Striatal infarction was equivalent, 12.2Ϯ1.7 mm 3 in ER␣KO and 13.4Ϯ1.0 mm 3 in WT mice, but cortical infarction was paradoxically smaller relative to that of the WT (20.7Ϯ4.5 mm 3 in ER␣KO versus 30.6Ϯ4.1 mm 3 in WT). Intraocclusion blood flow to the parietal cortex was higher in ER␣KO than in WT mice, likely accounting for the reduced infarction in this anatomic area. There were no differences in stroke outcomes by region or genotype in male animals. Conclusions-Loss of ER␣ does not enhance tissue damage in the female animal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype. (Stroke. 2000;31:738-744.)
2011
Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five OPEN ACCESS