Biomedical subjects

Sylvain Chemtob

Publications and source records attributed to Sylvain Chemtob.

At least 19 recordsLinked to original sources

PubMed2006

Lysophosphatidic acid induces endothelial cell death by modulating the redox environment.

Oxidant stress plays a significant role in hypoxic-ischemic injury to the susceptible microvascular endothelial cells. During oxidant stress, lysophosphatidic acid (LPA) concentrations increase. We explored whether LPA caused cytotoxicity to neuromicrovascular cells and the potential mechanisms thereof. LPA caused a dose-dependent death of porcine cerebral microvascular as well as human umbilical vein endothelial cells; cell death appeared oncotic rather than apoptotic. LPA-induced cell death was mediated via LPA(1) receptor, because the specific LPA(1) receptor antagonist THG1603 fully abrogated LPA's effects. LPA decreased intracellular GSH levels and induced a p38 MAPK/JNK-dependent inducible nitric oxide synthase (NOS) expression. Pretreatment with the antioxidant GSH precursor N-acetyl-cysteine (NAC), as well as with inhibitors of NOS [N(omega)-nitro-l-arginine (l-NNA); 1400W], significantly prevented LPA-induced endothelial cell death (in vitro) to comparable extents; as expected, p38 MAPK (SB203580) and JNK (SP-600125) inhibitors also diminished cell death. LPA did not increase indexes of oxidation (isoprostanes, hydroperoxides, and protein nitration) but did augment protein nitrosylation. Endothelial cytotoxicity by LPA in vitro was reproduced ex vivo in brain and in vivo in retina; THG1603, NAC, l-NNA, and combined SB-203580 and SP600125 prevented the microvascular rarefaction. Data implicate novel properties for LPA as a modulator of the cell redox environment, which partakes in endothelial cell death and ensued neuromicrovascular rarefaction.

Animals↗

PubMed2006

Hyperoxic exposure leads to nitrative stress and ensuing microvascular degeneration and diminished brain mass and function in the immature subject.

BACKGROUND AND PURPOSE: Neonates that survive very preterm birth have a high prevalence of cognitive impairment in later life. A common factor detected in premature infants is their postnatal exposure to high oxygen tension relative to that in utero. Hyperoxia is known to elicit injury to premature lung and retina. Because data on the exposure of the brain to hyperoxia are limited, we studied the effects of high oxygen on this tissue. METHODS: Rat pups were exposed from birth until day 6 to 21% or 80% O(2). Cerebral vascular density was quantified by lectin immunohistochemistry. Immunoblots for several proteins were performed on brain extracts. We assessed cerebral functional deficits by visual evoked potentials. RESULTS: Exposure of pups to hyperoxia leads to cerebral microvascular degeneration, diminished brain mass, and cerebral functional deficits. These effects are preceded by an upregulation of endothelial nitric oxide synthase (eNOS) in cerebral capillaries and a downregulation of Cu/Zn superoxide dismutase (SOD). The imbalance in nitric oxide (NO) production and antioxidant defenses favors the formation of nitrating agents in the microvessels revealed by increased nitrotyrosine (3-nt) immunoreactivity and decreased expression of NF-kappaB and the dependent vascular endothelial growth factor receptor 2. NOS inhibitors and eNOS deletion as well as an SOD mimetic (CuDIPS) restore vascular endothelial growth factor receptor-2 levels and nearly abolish the vasoobliteration. NOS inhibitors and SOD mimetic also prevent O(2)-induced diminished brain mass and functional deficit. CONCLUSIONS: Data identify NO and nitrating agents as major mediators of cerebral microvascular damage, ensuing impaired brain development and function in immature subjects exposed to hyperoxia.

Age Factors↗

PubMed2006

Structural and functional consequences of bright light exposure on the retina of neonatal rats.

In a previous study we showed that juvenile rats exposed, for various durations of time, to a bright luminous environment between P14 (eye opening) and P34 developed a light-induced retinopathy (LIR), the severity of which depending on the duration of exposure as well as the age of the rat at the onset of exposure. Our study also revealed that the severity of the LIR increased as the time elapsed between the cessation of exposure and the structural/functional evaluation increased, suggesting that the LIR degenerative process proceeded in two distinct steps namely, an initial (rapid) acute phase that was followed by a (slower) chronic phase. In view of the above, the purpose of the present study was to reinvestigate previous claims suggesting that exposure to bright light prior to eyelid opening had no measurable consequences on the retinal structure and function; the claim being that despite a non-detectable acute phase, bright light exposure prior to eyelid opening could nonetheless yield a significant retinopathy during the chronic phase of development of LIR. In order to test our hypothesis, neonatal rats were raised in a bright luminous environment from birth to P14. At P30, analysis of the results obtained from rats exposed between P0-P14 did not reveal, as previously acknowledged by others, significant LIR damages. However, results obtained at P60 disclosed significant functional anomalies with relative sparing of the retinal ultrastructure. Our results confirm that, in spite of closed eyelids, postnatal exposure to bright environment did trigger a slow degenerative process.

Animals↗

PubMed2006

Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1.

Stimulation of freshly isolated rat hepatocytes with lysophosphatidic acid (LPA) resulted in LPA1 receptor-mediated and nitricoxide-dependent up-regulation of the immediate early genes iNOS (inducible nitric-oxide synthase (NOS)) and mPGES-1 (microsomal prostaglandin E synthase-1). Because LPA is a ligand for both cell surface and intracellular receptor sites and a potent endothelial NOS (eNOS) activator, we hypothesized that NO derived from activated nuclearized eNOS might participate in gene regulation. Herein we show, by confocal microscopy performed on porcine cerebral endothelial cells expressing native LPA1-receptor and eNOS and on HTC4 rat hepatoma cells co-transfected with recombinant human LPA1-receptor and fused eNOS-GFP cDNA, a dynamic eNOS translocation from peripheral to nuclear regions upon stimulation with LPA. Nuclear localization of eNOS and its downstream effector, soluble guanylate cyclase, were demonstrated in situ in rat liver specimens by immunogold labeling using specific antibodies. Stimulation of this nuclear fraction with LPA and the NO donor sodium nitroprusside resulted, respectively, in increased production of nitrite (and eNOS phosphorylation) and cGMP; these separate responses were also correspondingly blocked by NOS inhibitor L-NAME and soluble guanylate cyclase inhibitor ODQ. In addition, sodium nitroprusside evoked a sequential increase in nuclear Ca2+ transients, activation of p42 MAPK, NF-kappaB binding to DNA consensus sequence, and dependent iNOS RNA. This study describes a hitherto unrecognized molecular mechanism by which nuclear eNOS through ensuing NO modulates nuclear calcium homeostasis involved in gene transcription-associated events. Moreover, our findings strongly support the concept of the nucleus as an autonomous signaling compartment.

Animals↗

PubMed2006

Proangiogenic effects of protease-activated receptor 2 are tumor necrosis factor-alpha and consecutively Tie2 dependent.

OBJECTIVE: Angiogenesis is essential physiologically in growth and pathologically in tumor development, chronic inflammatory disorders, and proliferative retinopathies. Activation of protease-activated receptor 2 (PAR2) leads to a proangiogenic response, but its mechanisms have yet to be specifically described. Here, we investigated the mode of action of PAR2 in retinal angiogenesis. METHODS AND RESULTS: PAR2-activating peptide, SLIGRL, increased retinal angiogenesis associated with an induction of vascular endothelial growth factor and angiopoetin-2 and most notably tie2 in the retina in vivo as well as in cultured neuroretinal endothelial cells. SLIGRL also induced release of the proinflammatory and angiogenic mediator tumor necrosis factor-alpha (TNF-alpha) via the MEK/extracellular signal-regulated kinase (ERK) (MEK/ERK) pathway in these endothelial cells. TNF-alpha, in turn, elicited tie2 expression by activating the MEK/ERK pathway. PAR2-evoked tie2 expression, endothelium proliferation (in vitro), and retinal neovascularization (in vivo) were abrogated by selective TNF-alpha blockers (neutralizing antibody infliximab and soluble TNF-alpha receptor-Fc fusion protein etanercept) as well as the MEK inhibitor PD98059. CONCLUSIONS: The proangiogenic properties of PAR2 are intertwined with its proinflammatory effects, such that in retinal vasculature, they depend on TNF-alpha and subsequent induction of tie2 via the MEK/ERK pathway.

Angiopoietin-2↗

PubMed2006

Hypercapnia- and trans-arachidonic acid-induced retinal microvascular degeneration: implications in the genesis of retinopathy of prematurity.

High oxygen tension is a major factor in the genesis of retinopathy of prematurity (ROP). However, clinical and experimental evidence suggests a significant role for high carbon dioxide (CO(2)) tension as well. Along these lines, although ischemia is often considered to be synonymous with an oxygen deficit, it is also associated with a concomitant local elevation of CO(2) that can lead to impaired developmental and ischemic neovascularization. The mechanisms by which hypercapnia induces retinal microvascular degeneration, a critical step which precedes the subsequent proliferative preretinal neovascularization, are not known. Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as ROP. Hypercapnia is a facilitator of nitration in vitro. We hereby present evidence that prolonged exposure to CO(2) impairs developmental retinal neovascularization through a mechanism involving increased endothelial nitric oxide synthase and induction of a nitrative stress; effects of hypercapnia are independent of its hyperaemic effects. Moreover, we demonstrate that an in vivo nitrative stress associated with retinal vasoobliteration results in nitration of arachidonic acids into trans-arachidonic acids (TAAs), which can act as mediators of nitrative stress by causing microvascular degeneration by inducing expression of the antiangiogenic factor thrombospondin-1. These recent findings establish a previously unexplored means by which hypercapnia hinders efficient neovascularization and provide new insight into the molecular mechanisms of nitrative stress on microvascular injury involving TAA, and suggest new therapeutic avenues in the management of nitrative stress disorders such as in ischemic retinopathies (of prematurity and of diabetes) and encephalopathies.

Animals↗

PubMed2006

Field stimulation-induced tetrodotoxin-resistant vasorelaxation is mediated by sodium hypochlorite.

This study was done to determine the mechanism of field stimulation-induced tetrodotoxin (TTX)- and NG- nitro-l-arginine (LNA)-resistant vasorelaxation. Field stimulation with platinum and carbon, but not with silver, electrodes (30 V, 30 HZ, 2-5 ms pulse width) as well as electrically stimulated salt (0.9% NaCl) solution (ESSS) or Krebs solution caused 100% relaxation of phenylephrine-contracted rat aortic strips, which was TTX and LNA resistant and endothelium independent. ESSS also relaxed other vascular preparations (rabbit aorta and renal artery, dog coronary artery, pig ductus arteriosus, and rat portal vein). The electric current generated hypochlorite (OCl-) and H2O2 from the salt solution; however, vasorelaxation was caused by NaOCl and not by H2O2. ESSS and NaOCl caused contraction failure of spontaneously beating right atria of rats and did not affect uterine contractions, vascular cAMP, cGMP, or the pH of the tissue bath. Field stimulation, ESSS, and NaOCl did not relax aortic preparations contracted by 32 mmol/L potassium and their vasorelaxant effects on phenylephrine-contracted rat aortic strips and rings were completely reversed by tetraethylammonium and partially by glibenclamide and iberiotoxin. We conclude that electric pulses generate the oxidant OCl- from the salt solution, which causes vasorelaxation by increasing K+ conductance.

Animals↗

PubMed2006

Structural and functional consequences of trolox C treatment in the rat model of postnatal hyperoxia.

PURPOSE: Previous studies have shown that newborn rats exposed to hyperoxia within the first 2 weeks of life develop vasculopathy in addition to permanent changes in retinal structure and function. It has also been suggested that free radicals may be the source of these pathologic effects. Trolox C, a water-soluble analogue of vitamin E, was previously shown to limit the vascular consequences of exposure to postnatal hyperoxia. The aim of this study was to investigate whether trolox C could also help prevent the functional (electroretinography) and structural (retinal histology) consequences associated with oxygen-induced retinopathy (OIR). METHODS: Newborn albino Sprague-Dawley rats exposed or not exposed to hyperoxia received daily injections of trolox C in doses of 300, 600, and 900 microg/kg (total volume, 50 microL). The effect of treatment was evaluated through electroretinography and retinal histology. RESULTS: Although trolox C tended to have a retinoactive effect on the normal retina, normalization of the hyperoxia-treated group to hyperoxic control and of the normoxia-treated group to normoxic control revealed that the a-wave remained relatively unaffected by hyperoxia exposure and by treatment with trolox C, the efficacy of trolox C at doses of 600 and 900 microg/kg largely outweighed the retinoactive effect, and the oscillatory potentials (OPs) benefited to the greatest extent from trolox C treatment. Furthermore, trolox C was able to limit the reduction in outer plexiform layer thickness but not the concomitant reduction of the horizontal cell count, each of which is associated with OIR. CONCLUSIONS: These results show that, as had been previously demonstrated with retinal vasculature, trolox C limited the retinal functional and structural damages inherent in the rat model of OIR. However, despite treatment, there were still signs (albeit less severe) indicative of OIR. This suggests, as previously advanced, that the pathophysiology of OIR is not solely caused by the action of free radicals or that trolox C is inadequate in treating all aspects of OIR.

Animals↗

PubMed2006

Light-induced retinopathy: comparing adult and juvenile rats.

PURPOSE: To investigate the effect of chronic exposure to a bright, luminous environment, starting at the opening of the eyes, on the retinal structure and function of the suckling rat. METHODS: Juvenile Sprague-Dawley rats were exposed to 10,000 lux, for varying lengths of time between postnatal day (P)14 and P34. Results were compared with those obtained from adult rats exposed to the same light intensity and for the same duration. Electroretinograms (ERGs) were recorded at 1 month and 2 months of age, after which the retinas were harvested for histologic analysis. RESULTS: In juvenile rats, the severity of light-induced retinopathy (LIR) depended not only on the duration of the exposure but, more important, on the age of the rat at the onset of exposure. For example, in adult rats, 6-day exposure reduced the thickness of the outer nuclear layer (ONL) to less than 18% of normal, whereas in juvenile rats, 6-day exposure between P14 and P20 reduced it to 50% compared with 27% after exposure between P28 and P34. An adultlike effect could only be evidenced in rats exposed at the end of the first postnatal month (P28-P34). A similar age-dependent effect was also noted on the electroretinogram. CONCLUSIONS: These results show that, compared with the mature retina, the developing retina appears to be relatively preserved from the devastating consequences of exposure to bright light. This window of resistance to light damage gradually weakens as the juvenile rat approaches its 1-month anniversary.

Animals↗

PubMed2006

Potential role of microglia in retinal blood vessel formation.

PURPOSE: The role of microglia, present in the retina early in development before vascularization, remains ill defined. The authors investigated whether microglia are implicated in retinal blood vessel formation. METHODS: The microglia and vasculature of developing human fetal and rodent retinas were examined by labeling the endothelial cells with lectin and the microglia with CD18 antibody or green fluorescent protein driven by the promoter of the chemokine receptor CX(3)CR1. Rodent ischemic proliferative retinopathy induced by hyperoxia or hypercapnia, which model retinopathy of prematurity, and ex vivo retinal explants were used to assess microglial involvement in vascular pathology. Microglial participation in developmental retinal vessel formation was further studied in neonatal rats after pharmacologic macrophage depletion with the use of clodronate liposomes and subsequent intravitreal injection of microglia. RESULTS: Microglia intimately appose developing vessels of human and murine retinas. Ischemic retinopathy models exhibit decreased microglia concomitant with the characteristic reductions in vasculature observed in these retinopathies. Retinal explants exposed to conditions resulting in ischemic retinopathies (in vivo) reveal that antioxidants protect against microglial loss. Depletion of resident retinal microglia, but not systemic macrophages, reduced developmental vessel growth and density, which were restored by intravitreal microglial injection. CONCLUSIONS: These observations suggest that proper retinal blood vessel formation requires an adequate resident microglial population because diminished microglia are associated with decreased vascularity in models of ischemic retinopathy and retinal vascular development. In light of these findings, the traditional definition of microglia as merely immunocompetent cells should be reconsidered to encompass this new function related to blood vessel formation.

Animals↗

PubMed2006

Activation of CD36 inhibits and induces regression of inflammatory corneal neovascularization.

PURPOSE: This study was undertaken to investigate the role of the antiangiogenic receptor CD36 during inflammatory corneal neovascularization (CNV). METHODS: In a murine model of inflammatory CNV, CD36 expression was evaluated by RT-PCR and immunofluorescence. Mice subjected to CNV were treated topically (thrice daily) with CD36 functionally neutralizing antibodies against the oxidized low-density lipoprotein (oxLDL) and thrombospondin (TSP)-1 sites (clones JC63.1 and FA6-152, respectively). Neovascularization was analyzed by CD31-immunostained corneal flatmounts. The role of the less characterized oxLDL site during angiogenesis was elucidated by using the CD36 ligand 1-palmitoyl 2-(5'-oxovaleroyl) phosphatidylcholine (POVPC; 50, 100 microg/mL) 24 hours after corneal injury for 7 days, whereas in angioregressive studies, POVPC treatments were initiated 10 days after induction of CNV. In this process, VEGF expression was also studied. Effects of CD36 activation were further examined ex vivo using the mouse aortic ring assay. RESULTS: CD36 expression was upregulated after corneal injury; CD36 was expressed in corneal epithelium, limbus, invading microvessels, and stromal macrophages. Blocking CD36 activity with FA6-152 significantly increased CNV (P <0.001). Conversely, activating CD36 with POVPC dose dependently inhibited CNV (P = 0.003); this effect was blocked by JC61.3. POVPC also significantly regressed preformed blood vessels (P < 0.001). Ex vivo experiments on aortic rings confirmed the angioinhibitory and -regressive effects of POVPC. Because corneal macrophages express CD36 and may partake in angiogenesis via VEGF-A secretion, we surmised that VEGF-A could be modulated by CD36. Indeed, POVPC downregulated VEGF-A expression in a time-dependent fashion (P < 0.001), whereas FA6-152 induced its expression (P < 0.05). CONCLUSIONS: CD36 is involved both physiologically and pharmacologically in inhibition and regression of CNV, by direct effect on endothelial cells and partly by negatively regulating VEGF expression in macrophages.

Animals↗

PubMed2005

Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration.

Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO(2)(*)-mediated isomerization of arachidonic acid within the cell membrane, but their biological relevance is unknown. Here we show that trans-arachidonic acids are generated in a model of retinal microangiopathy in vivo in a NO(*)-dependent manner. They induce a selective time- and concentration-dependent apoptosis of microvascular endothelial cells in vitro, and result in retinal microvascular degeneration ex vivo and in vivo. These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism. Our findings provide new insight into the molecular mechanisms of nitrative stress in microvascular injury and suggest new therapeutic avenues in the management of disorders involving nitrative stress, such as ischemic retinopathies and encephalopathies.

Animals↗

PubMed2005

Hypercapnia prevents neovascularization via nitrative stress.

Neovascularization after an ischemic insult is a beneficial attempt to salvage the injured tissue. Yet, despite the production of angiogenic factors within ischemic tissues, compensatory growth of new vessels fails to provide adequate vascularization. Thus, we hypothesized that local factors counter efficient revascularization. Whereas ischemia is often considered to be synonymous with an oxygen deficit, it is also associated with a concomitant local elevation of carbon dioxide (CO2). Although studies suggest that hypercapnia impacts tissue neovascularization, its significance relative to the abundantly described effects of hypoxia and its underlying mechanisms have yet to be elucidated. Therefore, we investigated the effects of hypercapnia on blood vessel growth in models of developmental and ischemic neovascularization. Acute and prolonged CO2 exposure inhibited developmental neovascularization of the rodent retina, as well as revascularization of the ischemic retina. Hypercapnia induced early increases in endothelial nitric oxide synthase and nitrative stress, associated with astrocyte impairment and endothelial cell death, as well as downregulation of the proangiogenic prostaglandin E2 receptor EP3. These results establish a previously unexplored means by which hypercapnia hinders efficient neovascularization, a mechanism that may contribute to ischemic tissue injury.

Animals↗

PubMed2005

Dominant role for calpain in thromboxane-induced neuromicrovascular endothelial cytotoxicity.

Thromboxane A(2) (TXA(2)) is an important lipid mediator generated during oxidative stress and implicated in ischemic neural injury. This autacoid was recently shown to partake in this injury process by directly inducing endothelial cytotoxicity. We explored the mechanisms for this TXA(2)-evoked neural microvascular endothelial cell death. Stable TXA(2) mimetics 5-heptenoic acid, 7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-[1R-[1alpha,4alpha,5beta(Z),6alpha,(1E,3S)]]-9,11-dedioxy-9alpha,11alpha-methanolpoxy (U-46619) [as well as [1S-[1alpha,2alpha(Z),3beta(1E,3S(*)),4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.1.1]-hept-2-yl]-5-heptenoic acid; I-BOP] induced a retinal microvascular degeneration in rat pups in vivo and in porcine retinal explants ex vivo and death of porcine brain endothelial cells (in culture). TXA(2) dependence of these effects was corroborated by antagonism using the selective TXA(2) receptor blocker (-)-6,8-difluoro-9-p-methyl-sulfonyl-benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596). In all cases, neurovascular endothelial cell death was prevented by pan-calpain and specific m-calpain inhibitors but not by caspase-3 or pan-caspase inhibitors. Correspondingly, TXA(2) (mimetics) augmented generation of known active m-calpain (but not mu-calpain) form and increased the activity of m-calpain (cleavage of fluorogenic substrate N-succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin; and of alpha-spectrin into specific fragments) but not of pan-caspase or specific caspase-3 (respectively, using sulforhodamine-Val-Arg-Asp-fluoromethyl ketone and detecting its active 17- and 12-kDa fragments). Interestingly, these effects were phospholipase C (PLC)-dependent [associated with increase in inositol triphosphate and inhibited by PLC blocker 1-[6-[[17beta-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122)] and required calcium but were not associated with increased intracellular calcium. U-46619-induced calpain activation resulted in translocation of Bax to the mitochondria, loss of polarization of the latter (using potentiometric probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide; JC-1) and in turn release of cytochrome c into the cytosol and depletion of cellular ATP; these effects were all blocked by calpain inhibitors. Overall, this work identifies (specifically) m-calpain as a dominant protease in TXA(2)-induced neurovascular endothelial cell death.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

New insights into the retinal circulation: inflammatory lipid mediators in ischemic retinopathy.

Ischemic proliferative retinopathy develops in various retinal disorders, including retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity. Ischemic retinopathy remains a common cause of visual impairment and blindness in the industrialized world due to relatively ineffective treatment. Oxygen-induced retinopathy (OIR) is an established model of retinopathy of prematurity associated with vascular cell injury culminating in microvascular degeneration, which precedes an abnormal neovascularization. The retina is a tissue particularly rich in polyunsaturated fatty acids and the ischemic retina becomes highly sensitive to lipid peroxidation initiated by oxygenated free radicals. Consequently, the retina constitutes an excellent model for testing the functional consequences of membrane lipid peroxidation. Retinal tissue responds to physiological and pathophysiological stimuli by the activation of phospholipases and the consequent release from membrane phospholipids of biologically active metabolites. Activation of phospholipase A(2) is the first step in the synthesis of two important classes of lipid second messengers, the eicosanoids and a membrane-derived phospholipid mediator platelet-activating factor (PAF). These lipid mediators accumulate in the retina in response to injury and a physiologic role of these metabolites in retinal vasculature remains for the most part to be determined; albeit proposed roles have been suggested for some. The eicosanoids, in particular the prostanoids, thromboxane (TXA2) and PAF are abundantly generated following an oxidant stress and contribute to neurovascular injury. TXA2 and PAF play an important role in the retinal microvacular degeneration of OIR by directly inducing endothelial cell death and potentially could contribute to the pathogenesis of ischemic retinopathies. Despite these advances there are still a number of important questions that remain to be answered before we can confidently target pathological signals. This review focuses on mechanisms that precede the development of neovascularization, most notably regarding the role of lipid mediators that partake in microvascular degeneration.

Endothelial Cells↗

PubMed2005

Inflammatory lipid mediators in ischemic retinopathy.

Ischemic proliferative retinopathy develops in various retinal disorders, including retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity. Ischemic retinopathy remains a common cause of visual impairment and blindness in the industrialized world due to relatively ineffective treatment. Oxygen-induced retinopathy (OIR) is an established model of retinopathy of prematurity associated with vascular cell injury culminating in microvascular degeneration, which precedes an abnormal neovascularization. The retina is a tissue particularly rich in polyunsaturated fatty acids and the ischemic retina becomes highly sensitive to lipid peroxidation initiated by oxygenated free radicals. Retinal tissue responds to physiological and pathophysiological stimuli by the activation of phospholipases and the consequent release from membrane phospholipids of biologically active metabolites. Activation of phospholipase A(2) is the first step in the synthesis of two important classes of lipid second messengers, the eicosanoids and a membrane-derived phospholipid mediator platelet-activating factor (PAF). These lipid mediators accumulate in the retina in response to injury and a physiologic role of these metabolites in retinal vasculature remains for the most part to be determined; albeit proposed roles have been suggested for some. The eicosanoids, in particular the prostanoids, thromboxane A(2) (TXA(2)) and PAF are abundantly generated following an oxidant stress and contribute to neurovascular injury. TXA(2) and PAF play an important role in the retinal microvacular degeneration of OIR by directly inducing endothelial cell death and potentially could contribute to the pathogenesis of ischemic retinopathies. This review focuses on mechanisms that precede the development of neovascularization, most notably regarding the role of lipid mediators that partake in microvascular degeneration.

Animals↗

PubMed2004

The pharmacologic closure of the patent ductus arteriosus.

The ductus arteriosus is a fetal vessel that allows most of the blood leaving the right ventricle of the heart to bypass the lungs. Fetal patency of the ductus, and its spontaneous closure after birth, is the result of a balanced interaction of locally produced and circulating mediators (of which prostaglandins seem to be the most important), and the unique structure of the vessel wall. Persistent patency of the ductus occurs in almost 60% of very low birthweight infants. A significant left-to-right shunt through the ductus increases morbidity and mortality in premature infants. As prostaglandins play a major role in patency of the ductus, cyclooxygenase inhibitors are conventionally used to induce its closure. This chapter focuses on some of the basic mechanisms underlying ductal patency and the clinical attempts to diminish side effects associated with indomethacin, including the alternative use of ibuprofen.

Cyclooxygenase Inhibitors↗

PubMed2004

Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathy.

Opposing effects have been ascribed to nitric oxide (NO) on retinal microvascular survival. We investigated whether changes in the redox state may contribute to explain apparent conflicting actions of NO in a model of oxygen-induced retinal vasoobliteration. Retinal microvascular obliteration was induced by exposing 7-day-old rat pups (P7) for 2 or 5 days to 80% O(2). The redox state of the retina was assessed by measuring reduced glutathione and oxidative and nitrosative products malondialdehyde and nitrotyrosine. The role of NO on vasoobliteration was evaluated by treating animals with nitric oxide synthase (NOS) inhibitors (N-nitro-l-arginine; L-NA) and by determining NOS isoform expression and activity; the contribution of nitrosative stress was also determined in animals treated with the degradation catalyst of peroxynitrite FeTPPS or with the superoxide dismutase mimetic CuDIPS. eNOS, but not nNOS or iNOS, expression and activity were increased throughout the exposure to hyperoxia. These changes were associated with an early (2 days hyperoxia) decrease in reduced glutathione and increases in malondialdehyde and nitrotyrosine. CuDIPS, FeTPPS, and L-NA treatments for these 2 days of hyperoxia nearly abolished the vasoobliteration. In contrast, during 5 days exposure to hyperoxia when the redox state rebalanced, L-NA treatment aggravated the vasoobliteration. Interestingly, VEGFR-2 expression was respectively increased by NOS inhibition after short-term (2 days) exposure to hyperoxia and decreased during the longer hyperoxia exposure. Data disclose that the dual effects of NO on newborn retinal microvascular integrity in response to hyperoxia in vivo depend on the redox state and seem mediated at least in part by VEGFR-2.

Animals↗