Expression and Vascular Effects of Cyclooxygenase-2 in Brain

Brian, Johnny E.; Moore, Steven A.; Faraci, Frank M.

doi:10.1161/01.str.29.12.2600

Cited by 45 publications

(38 citation statements)

References 49 publications

(42 reference statements)

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“…However, we found that DEX treatment had no significant effects on COX-1 or -2 protein expression in our samples ( fi g. 4 ). Our data supports the fi ndings of Heinonen et al [9] , Brian et al [28] , and Weidenfeld et al [29] which showed that although DEX decreased vasodilatory prostanoids or arterial diameter in animals exposed to hypercapnia, endotoxin, or lipopolysaccharide treatment, DEX treatment had no effect on baseline levels of COX, vasodilator prostanoids, or lumen size under normocapneic conditions. In addition, studies from Inoue et al [30] showed that glucocorticoid-mediated suppression of COX was dose-and endothelium-dependent , suggesting that DEX at clinically relevant doses applied to endothelium-denuded arteries may not affect COX protein levels.…”

Section: Discussionsupporting

confidence: 92%

Dexamethasone Alters Vascular Reactivity by Enhancing COX-Related Vasodilatation in Fetal Ovine Carotids

Angeles

Chang²,

Leong³

et al. 2006

Neonatology

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Based on preliminary studies that contractile efficacy was altered in vertebral and basilar arteries from neonatal donors treated with postnatal glucocorticoids, we examined the hypothesis that postnatal dexamethasone (DEX), a glucocorticoid used for respiratory disease in neonates, can alter vascular reactivity. Using near-term fetal lamb carotids, we measured 5-hydroxytryptamine (5-HT) dose-response relationship in DEX-treated and untreated arteries. We found that DEX incubation for 1 h had no effect on 5-HT sensitivity and agonist affinity but significantly reduced 5-HT contractile efficacy, a response that became even more pronounced after 4 h of DEX treatment. Coincubation of DEX-treated arteries with INDO for 4 h reversed this DEX-induced attenuation in 5-HT contractile efficacy, although DEX had no significant effects on cyclooxygenase (COX)-1 and COX-2 protein abundance. This data suggests that DEX alters vascular reactivity through a COX-related mechanism, with possible repercussions to neurological injury.

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Section: Discussionsupporting

confidence: 92%

Dexamethasone Alters Vascular Reactivity by Enhancing COX-Related Vasodilatation in Fetal Ovine Carotids

Angeles

Chang²,

Leong³

et al. 2006

Neonatology

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“…These findings suggest that estrogen reduced IL-1␤-mediated endothelial-dependent cerebral vasodilation; this would perhaps be manifest as diminished hyperemia in the in vivo situation (23). Based on the results of others (3,5,31,36), we suspected that the IL-1␤-mediated decrease in cerebrovascular tone was perhaps governed by COX-2-derived PGE 2 . The endothelial localization of COX-2, the known vasodilatory effects of PGE 2 (14), and the decrease in PGI 2 after IL-1␤ treatment all support this hypothesis.…”

Section: Discussionmentioning

confidence: 59%

Estrogen suppresses IL-1β-mediated induction of COX-2 pathway in rat cerebral blood vessels

Ospina

Brevig

Krause

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Ospina, Jose A., Holly N. Brevig, Diana N. Krause, and Sue P. Duckles. Estrogen suppresses IL-1␤-mediated induction of COX-2 pathway in rat cerebral blood vessels. Am J Physiol Heart Circ Physiol 286: H2010-H2019, 2004. First published December 18, 2003 10.1152/ajpheart.00481.2003.-Interleukin (IL)-1␤ is a potent inducer of inflammatory prostaglandins, which are important mediators of vascular response to cerebral injury, whereas estrogen reduces brain injury in models of ischemic stroke. Thus we examined the effects of in vivo IL-1␤ exposure on cerebrovascular cyclooxygenase (COX)-2 expression and function in an animal model of chronic estrogen replacement. Estrogen-treated and nontreated ovariectomized female rats received IL-1␤ injections (10 g/kg ip), and then cerebral vessels were isolated for biochemical and contractile measurements. In estrogen-deficient rats, IL-1␤ induced cerebrovascular COX-2 protein expression; a peak response occurred 3 h after injection. COX-2 was localized to arterial endothelium using confocal microscopy. IL-1␤ increased PGE2 but not PGI2 production and decreased vascular tone as measured in isolated cerebral arteries; the latter effect was partially reversed by treatment with the selective COX-2 inhibitor NS-398 (10 mol/l). In contrast, in animals treated with estrogen, IL-1␤ had no significant effect on COX-2 protein levels, PGE2 production, or vascular tone. Combined treatment with 17␤-estradiol and medroxyprogesterone acetate also prevented increases in PGE2 production after IL-1␤ treatment, but treatment with 17␣-estradiol had no effect. IL-1␤ induction of COX-2 protein was prevented by treatment with the nuclear factor-B inhibitor caffeic acid phenethyl ester (20 mg/kg ip), and estrogen treatment reduced cerebrovascular nuclear factor-B activity. Estrogen thus has potent anti-inflammatory effects with respect to cerebral vascular responses to IL-1␤. These effects may have important implications for the incidence and severity of cerebrovascular disease.17␤-estradiol; cyclooxygenase-2; prostaglandin E 2; nuclear factor-B; interleukin-1␤

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“…PGE 2 , PGI 2 , TxA 2 , and PGF 2␣ are known to be vasoactive in the fetal brain (22). In the present study, arterial plasma concentrations of PGE 2 and 6-keto-PGF 1␣ (a stable metabolite of PGI 2 ) were measured as known potent vasodilators (15,30,31). TxB 2 (a stable …”

Section: Discussionmentioning

confidence: 81%

Role of Prostanoids in the Regulation of Cerebral Blood Flow During Normoxia and Hypoxia in the Fetal Sheep

et al. 2006

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ABSTRACT:The fetal cardiovascular responses to hypoxia include decreased peripheral blood flow and increased cerebral, cardiac, and adrenal blood flow. Prostanoids, metabolites of cyclooxygenase enzyme activity, have potent effects on vascular tone in both the adult and the fetus. To examine the role of prostanoids in the regulation of fetal cerebral blood flow (CBF) during acute hypoxic stress, eight near term fetal sheep were studied after infusing vehicle or diclofenac, a cyclooxygenase inhibitor, followed by a 30-min period of hypoxia (arterial PO 2 12 Torr). In the control experiments, CBF, measured continuously with laser Doppler flowmetry, increased to 148% of baseline values (p Ͻ 0.01) and cerebral vascular resistance decreased to 70% of baseline values after 30 min of hypoxic stress. During diclofenac infusion, hypoxia resulted in a CBF increase to only 129% of baseline, a significant attenuation (p Ͻ 0.05), accompanied by decreased plasma prostanoid concentrations. Increases in mean arterial blood pressure during hypoxia were also attenuated by diclofenac infusion. Flow and pressure responses were not accompanied by changes in cerebral vascular resistance. These results indicate that prostanoids indirectly modulate fetal CBF responses to hypoxia, but that their effects are mediated through modulation of systemic rather than cerebral vascular tone. T he fetus is often subjected to hypoxic insult during gestation and labor. In defense against hypoxic injury, mechanisms come into play that optimize the balance between oxygen delivery and consumption in vital organs such as the brain, heart, and adrenals. In the fetal brain, this is accomplished in part by an increase in CBF (1-3), a regulated reduction in oxidative metabolism (4 -6), and an increase in anaerobic metabolism. This increase in CBF is accomplished in part by redistribution of blood flow during hypoxic stress resulting in increased blood flow to vital organs and decreased blood flow to peripheral organs (1). The redistribution of flow to these organs is the result of increased systemic arterial blood pressure and decreased local cerebral vascular resistance (1,7). Previous work by our group and others has shown that both adenosine and nitric oxide are important mediators of this effect (5,6). However, the changes in CBF and vascular resistance during hypoxia cannot be completely attributed to these systems. The studies presented here focus on the role of prostanoids in mediating these changes in blood flow to the fetal brain during hypoxia.Prostanoids, a subclass of eicosanoids that includes prostaglandins and thromboxanes, are found throughout biologic tissues and are important modulators of vascular tone. Prostanoids are synthesized by oxidation of free arachidonic acid, a reaction catalyzed by cyclooxygenase enzymes cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). In adult vascular tissues, COX-1 is a constitutive enzyme, whereas COX-2 is an inducible enzyme, both of which are involved in the production of precursors of the vasoconstr...

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Expression and Vascular Effects of Cyclooxygenase-2 in Brain

Cited by 45 publications

References 49 publications

Dexamethasone Alters Vascular Reactivity by Enhancing COX-Related Vasodilatation in Fetal Ovine Carotids

Dexamethasone Alters Vascular Reactivity by Enhancing COX-Related Vasodilatation in Fetal Ovine Carotids

Estrogen suppresses IL-1β-mediated induction of COX-2 pathway in rat cerebral blood vessels

Role of Prostanoids in the Regulation of Cerebral Blood Flow During Normoxia and Hypoxia in the Fetal Sheep

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