Augmented Vasoconstriction and Thromboxane Formation by 15-F
            <sub>2t</sub>
            -Isoprostane (8-Iso-Prostaglandin F
            <sub>2α</sub>
            ) in Immature Pig Periventricular Brain Microvessels

Hou, Xin; Gobeil, Fernand; Peri, Krishna G.; Speranza, Giovanna; Marrache, Anne Marilise; Lachapelle, Pierre; Roberts, Jackson; Varma, Daya R.; Chemtob, Sylvain

doi:10.1161/01.str.31.2.516

Cited by 72 publications

(90 citation statements)

References 49 publications

(51 reference statements)

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“…PROSTANOIDS AND FETAL CEREBRAL BLOOD FLOW metabolite of TxA 2 ) was measured as a known potent vasoconstrictor (16,32,33). Although hypoxia may induce tissuespecific changes in prostanoid production, arterial plasma concentrations of PGE 2 , 6-keto-PGF 1␣ , and TxB 2 were not affected by hypoxia in this study, a finding consistent with previous reports (15,23).…”

supporting

confidence: 90%

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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supporting

confidence: 90%

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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“…19,22 Oxidative stress increases the formation of proinflammatory lipids 23,24 and isoprostanes 21,25 that are key elements of coronary artery disease 19 and impaired vasodilation. 21,25 In this regard, it is interesting to note that systemic concentrations of isoprostanes are increased in SCD. 21 Whether or not L-4F decreases the formation of proinflammatory lipids in SCD to protect endothelium-dependent vasodilation remains to be determined in future studies.…”

Section: Discussionmentioning

confidence: 99%

L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease

et al. 2003

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Background-Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O 2 ·Ϫ ) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr Ϫ/Ϫ ) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O 2 ·Ϫ generation. Methods and Results-Arterioles were isolated from hypercholesterolemic LdlrϪ/Ϫ mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O 2 ·Ϫ generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr Ϫ/Ϫ mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O 2 ·Ϫ in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice. Conclusions-These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD.Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases. Clinical studies clearly indicate that HDL plays an important role in protecting vascular function against atherosclerosis. 8 Transgenic expression of apoA-1, the major atheroprotective apolipoprotein of HDL, retards the progression of advanced lesions in transplanted aortas from apoE-null mice and remodels them to a more stable-appearing phenotype. 9 Intraperitoneal injection of an apoA-1 mimetic (5F) and parental administration of another apoA-1 mimetic (D-4F) enhances the ability of HDL to inhibit LDL oxidation and to protect mice from diet-induced atherosclerosis without changing plasma cholesterol levels. 6,10 Indeed, infusion of reconstituted HDL rapidly improves endothelium-and endothelial nitric oxide synthase (eNOS)-dependent forearm blood flow in hypercholesterolemic men, 11 confirming that HDL plays a critical role in protecting endothelial cell function.The mechanisms by which SCD have been shown to impair vasodilation at first glance appear distinctly different from tho...

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“…In contrast to prostaglandins produced by COX, isoprostanes are formed non-enzymatically in situ from the peroxidation of AA and then released by phospholipases; they exceed the production of prostaglandins under oxidizing conditions (27,53,65,66). Isoprostanes may contribute to microvascular injury in ROP, as they are indirectly cytotoxic, since they trigger the production of TXA 2 (68)(69)(70) (Figure 4). …”

Section: Figurementioning

confidence: 99%

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Sapieha¹,

Joyal²,

Rivera³

et al. 2010

J. Clin. Invest.

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213

225

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Retinopathy of prematurity (ROP) is a major complication of preterm birth. It encompasses a spectrum of pathologies that affect vision, from mild disease that resolves spontaneously to severe disease that causes retinal detachment and subsequent blindness. The pathologies are characterized by an arrest in normal retinal vascular development associated with microvascular degeneration. The resulting ischemia and retinal hypoxia lead to excessive abnormal compensatory blood vessel growth. However, this neovascularization can lead to fibrous scar formation and culminate in retinal detachment. Present therapeutic modalities to limit the adverse consequences of aberrant neovascularization are invasive and/or tissue-destructive. In this Review, we discuss current concepts on retinal microvascular degeneration, neovascularization, and available treatments, as well as present future perspectives toward more profound elucidation of the pathogenesis of ROP.Retinopathy of prematurity (ROP) is the major ocular disorder of the neonate (1, 2) and the dominant cause of severe visual impairment in childhood in North America and Europe. ROP is associated with significant sequelae, the most serious being retinal detachment, which results in blindness. However, even milder forms of ROP increase the incidence of pathologies that negatively impact visual acuity, for example, ametropias, refractive errors that reduce visual acuity; strabismus, a condition in which the eyes are not properly aligned, preventing proper binocular vision and adversely affecting depth perception; and disorders of color discrimination (3-6). ROP proceeds following an initial phase of degeneration of the retinal microvasculature (vasoobliteration) (7,8) (Figure 1) that is associated with cessation of progression of vascular growth toward the retinal periphery. In the subsequent phase of the disease, the ensuing retinal ischemia predisposes to abnormal compensatory neovascularization (9, 10). Of the various factors that have been associated with the development of ROP, low birth weight, low gestational age, supplemental oxygen therapy, and its associated relative hyperoxia dominate.The development of the human retinal vasculature commences at approximately the 16th week of gestation and concludes at term (i.e., the 40th week of gestation) (11). Hence, when an infant is born prematurely, its retinal blood supply is incomplete and highly vulnerable to decay. This immaturity in vascular development predisposes the retina to complications. Major advances have been made over the past 30 years in identifying mechanisms implicated in the genesis of ROP. Comprehension of mechanisms underlying this disorder has, in turn, enhanced understanding of the pathogenesis of ischemic retinal vasculopathies in the adult, for example, diabetic retinopathy (a complication of diabetes mellitus) and neovascular forms of age-related macular degeneration (the major cause of visual impairment in adults over 50 years of age).The oxygen-induced retinopathy (OIR) model of ischemic retinop...

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Augmented Vasoconstriction and Thromboxane Formation by 15-F _2t -Isoprostane (8-Iso-Prostaglandin F _2α ) in Immature Pig Periventricular Brain Microvessels

Cited by 72 publications

References 49 publications

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

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

L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

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Augmented Vasoconstriction and Thromboxane Formation by 15-F 2t -Isoprostane (8-Iso-Prostaglandin F 2α ) in Immature Pig Periventricular Brain Microvessels

Cited by 72 publications

References 49 publications

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

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

L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Contact Info

Product

Resources

About

Augmented Vasoconstriction and Thromboxane Formation by 15-F _2t -Isoprostane (8-Iso-Prostaglandin F _2α ) in Immature Pig Periventricular Brain Microvessels