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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human embryogenesis takes place in a hypoxic environment because the trophoblast shell excludes entry of maternal blood. The first fetal-placental villi develop as trophoblast sprouts. These are invaded by allantoic mesoderm to form secondary villi and are transformed, by vasculogenesis, into tertiary villi. The placental barrier to maternal blood is gradually breached between 8-12 weeks of gestation, due to invasion of placental-bed uteroplacental spiral arteries by the extravillous trophoblast (EVT). Placental oxygen tension thus rises and a phase of branching angiogenesis continues until 24 weeks. Thereafter a gradual shift takes place favoring non-branching angiogenesis. Gas-exchanging terminal villi thus form which are essential for rapid fetal growth and development of a high-flow, low-resistance fetal-placental circulation. Inadequate invasion of the uteroplacental spiral arteries by EVT results in placental ischemia and the development of obstetrical complications--preeclampsia and/or intrauterine growth restriction (IUGR). Placental villi often show evidence of continued branching angiogenesis, as is the case with anemic pregnancy, and pregnancy at high altitude. These structural alterations may reflect continued hypoxia-driven activity of vascular endothelial growth factor (VEGF). By contrast, a minority of severe early-onset IUGR pregnancies exhibit reduced fetal-placental blood flow with elongated maldeveloped villous capillaries. Placenta-like growth factor (PIGF) expression is increased while trophoblast proliferation is reduced, suggesting "hyperoxia" in the placental villous tree. IUGR may thus have two phenotypes--a more common hypoxic and a rarer hyperoxic type. While this concept is gaining acceptance, we have no insight as to the initiating mechanism(s).
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PMID:Oxygen and placental vascular development. 1063 6

Placental vascular diseases consist of obstetrical pathologies assumed to be linked to placental ischemia. Preeclampsia, defined as the association of hypertension, proteinuria and edema, occur in 3% of deliveries, in a non-selected population. Eclampsia, defined as the occurrence of convulsions in preeclamptic women, occur in 5 per 10,000 deliveries. Risk factors for preeclampsia are: preeclampsia in the previous pregnancy, maternal age <20 years, multiple pregnancies, and nulliparity. Placenta abruption, defined as premature separation of the placenta before delivery, occur in 5 to 15 per 1,000 deliveries. Risk factors are smoking, infertility, and preeclampsia or placental abruption in the previous pregnancy. Stillbirth, defined as fetal death between 24 weeks of gestation and delivery, occur in 1.5 per 1,000 deliveries, with a higher frequency in case of placental abruption, intrauterine growth restriction or preeclampsia.
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PMID:[Epidemiology of vascular placental disease]. 1502 84

Intrauterine growth restriction (IUGR) has a multifactorial pathogenesis and is an important cause of perinatal mortality. The relationship between fetal weight and placental blood flow in an animal model of IUGR has been investigated, showing that fetal growth is regulated by placental blood flow. The aim of the present study was to determine whether ischemia-reperfusion (I/R) injury stimulates the prostaglandin E2 (PGE2) system or the vascular endothelial growth factor (VEGF) system in the placenta of a rat IUGR model. COX-2 is reported to be involved in ischemic damage in many organs. There are 4 types of PGE2 receptor (EP1, EP2, EP3 and EP4). It is well known that EP1 and EP3 is associated with vasoconstriction. In the present study, vessels were occluded in the right uterine horn on day 17 of pregnancy in rats, and the clamps were removed after 30 min of ischemia. At 24h, 48 h, and 5 days after I/R injury, the live fetuses and placentas were obtained by cesarean section. This study revealed that I/R injury caused IUGR 5 days after the treatment. COX-2 expression and EP3 receptor expression were significantly elevated at 24h after I/R injury, but VEGF mRNA expression was not altered in the placenta from the ischemic horn compared with the non-ischemic horn. These results suggested that induction of the COX-2-EP3 system in the placenta may be one of the causes of IUGR induced by uterine ischemia, because the EP3 receptor and PGE2 are well known to mediate vasoconstriction in many organs.
Placenta
PMID:Elevation of both cyclooxygenase-2 and prostaglandin E2 receptor EP3 expressions in rat placenta after uterine artery ischemia-reperfusion. 1599 Jan 66

Hypoxia-inducible transcription factor-1alpha and -2alpha (HIF-alpha) proteins and regulated genes are increased in preeclamptic (PE) placentas. Although placental hypoxia likely stabilizes HIF-alpha proteins, we previously reported that there is also a defect in oxygen-dependent reduction of HIF-alpha proteins in PE relative to normal pregnant (NP) placentas that could contribute to their over-expression. After a 4-h exposure to 2% oxygen, placental villous explants were exposed to 21% oxygen over 90 min. As assessed by Western analysis, the defective oxygen-dependent reduction of HIF-1alpha protein in villous explants from PE placenta was unaffected by the protein synthesis inhibitor, cycloheximide. However, after incubation with the proteasomal inhibitor, clasto-lactacystin, oxygen-dependent reduction of HIF-1alpha protein was markedly and similarly impaired in the villous explants from both normal and PE placentas. Thus, impairment of protein degradation rather than increased synthesis causes inadequate oxygen-dependent reduction of HIF-1alpha protein in PE placentas. Immunoprecipitation studies revealed comparable association of HIF-1alpha with von Hippel Lindau (VHL) protein in placentas from NP and PE women. Furthermore, prolyl hydroxylase-3 protein was appropriately upregulated in the PE placentas as determined by Western analysis paralleling the increases of HIF-alpha proteins. These results suggest that molecular events leading to the formation of the HIF-1alpha:VHL:ubiquitin ligase complex are most likely not impaired in PE placentas. Finally, proteasomal trypsin, chymotrypsin, and peptidyl glutamyl-like activities were significantly reduced by approximately 1/3 in PE placentas by using specific peptide substrates coupled to a fluorescent tag. Unexpectedly, however, they were even further decreased in placentas from normotensive women delivering growth restricted babies >37 weeks gestation-placentas which do not have elevated HIF-alpha proteins. In conclusion, accumulation of HIF-alpha proteins in PE placentas may occur as a consequence of both increased formation secondary to relative ischemia/hypoxia and reduced degradation after reperfusion/oxygenation consequent to proteasomal dysfunction. In contrast, in placentas from normotensive women delivering growth restricted babies >37 weeks gestation, proteasomal activity, albeit markedly reduced, is adequate to cope with degradation of HIF-alpha proteins, which have not been increased by an hypoxic environment.
Placenta 2008 Mar
PMID:Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. 1822 38

Crucial roles of the placenta are disrupted in early and mid-trimester pregnancy loss, preeclampsia, eclampsia and intrauterine growth restriction. The pathophysiology of these disorders includes a relative hypoxia of the placenta, ischemia/reperfusion injury, an inflammatory response and oxidative stress. Reactive oxygen species including nitric oxide (NO), carbon monoxide and superoxide have been shown to participate in trophoblast invasion, regulation of placental vascular reactivity and other events. Superoxide, which regulates expression of redox sensitive genes, has been implicated in up-regulation of transcription factors, antioxidant production, angiogenesis, proliferation and matrix remodeling. When superoxide and nitric oxide are present in abundance, their interaction yields peroxynitrite a potent pro-oxidant, but also alters levels of nitric oxide, which in turn affect physiological functions. The peroxynitrite anion is extremely unstable thus evidence of its formation in vivo has been indirect via the occurrence of nitrated moieties including nitrated lipids and nitrotyrosine residues in proteins. Formation of 3-nitrotyrosine (protein nitration) is a "molecular fingerprint" of peroxynitrite formation. Protein nitration has been widely reported in a number of pathological states associated with inflammation but is reported to occur in normal physiology and is thought of as a prevalent, functionally relevant post-translational modification of proteins. Nitration of proteins can give either no effect, a gain or a loss of function. Nitration of a range of placental proteins is found in normal pregnancy but increased in pathologic pregnancies. Evidence is presented for nitration of placental signal transduction enzymes and transporters. The targets and extent of nitration of enzymes, receptors, transporters and structural proteins may markedly influence placental cellular function in both physiologic and pathologic settings.
Placenta 2008 Dec
PMID:Protein nitration in placenta - functional significance. 1885 82

In the dual ex vivo perfusion of an isolated human placental cotyledon it takes on average 20-30 min to set up stable perfusion circuits for the maternal and fetal vascular compartments. In vivo placental tissue of all species maintains a highly active metabolism and it continues to puzzle investigators how this tissue can survive 30 min of ischemia with more or less complete anoxia following expulsion of the organ from the uterus and do so without severe damage. There seem to be parallels between "depressed metabolism" seen in the fetus and the immature neonate in the peripartum period and survival strategies described in mammals with increased tolerance of severe hypoxia like hibernators in the state of torpor or deep sea diving turtles. Increased tolerance of hypoxia in both is explained by "partial metabolic arrest" in the sense of a temporary suspension of Kleiber's rule. Furthermore the fetus can react to major changes in surrounding oxygen tension by decreasing or increasing the rate of specific basal metabolism, providing protection against severe hypoxia as well as oxidative stress. There is some evidence that adaptive mechanisms allowing increased tolerance of severe hypoxia in the fetus or immature neonate can also be found in placental tissue, of which at least the villous portion is of fetal origin. A better understanding of the molecular details of reprogramming of fetal and placental tissues in late pregnancy may be of clinical relevance for an improved risk assessment of the individual fetus during the critical transition from intrauterine life to the outside and for the development of potential prophylactic measures against severe ante- or intrapartum hypoxia. Responses of the tissue to reperfusion deserve intensive study, since they may provide a rational basis for preventive measures against reperfusion injury and related oxidative stress. Modification of the handling of placental tissue during postpartum ischemia, and adaptation of the artificial reperfusion, may lead to an improvement of the ex vivo perfusion technique.
Placenta 2009 Mar
PMID:Tolerance of human placental tissue to severe hypoxia and its relevance for dual ex vivo perfusion. 1906 87

Preeclampsia (PE) is a pregnancy-specific disease that has been associated with future cardiovascular disease for the mother and her child. The etiology of PE is unclear but oxidative stress seems to play a major role in endothelial dysfunction and permanent systemic vasoconstriction shown in PE. Hydrogen peroxide (H(2)O(2)), a terminal metabolite of the cellular oxidative stress cascade, is also revealed as a component of oxidative ischemia/reperfusion stress in placenta. We were the first to show an increase in the levels of H(2)O(2) in the serum of preeclamptic women at term. H(2)O(2) is already known to reduce the production of NO by increasing the metabolism of arginases. The objective of this study was to investigate a possible correlation between nitric oxide (NO), a potent vasodilator, and H(2)O(2) throughout pregnancy. Thus, we simultaneously assessed the levels of NO and H(2)O(2) in the serum of normal and preeclamptic women at 10-15 and 37-40 weeks of pregnancy, and in placentas at delivery. Our findings showed an inverse correlation between increased levels of H(2)O(2) and decreased levels of NO early in maternal circulation and at term in placenta. This relationship is confirmed by our in vitro experiments which demonstrate that H(2)O(2) inhibits NO synthesis of cytotrophoblasts. In conclusion, our findings highlight an inverse correlation between H(2)O(2) and NO early in maternal circulation and in placenta of women with preeclampsia, paving the way for further studies examining the potential use of NO and H(2)O(2) as biomarkers in the prediction of preeclampsia.
Placenta 2009 Apr
PMID:Potential biomarkers of preeclampsia: inverse correlation between hydrogen peroxide and nitric oxide early in maternal circulation and at term in placenta of women with preeclampsia. 1922 72

Intrauterine growth restriction (IUGR) remains an important cause of perinatal morbidity and mortality. Both IUGR and low birth weight have been identified as risk factors for increased incidence of cardiovascular disease, dyslipemia, and other diseases in the adulthood. Several animal models have been developed to study the underlying mechanisms of IUGR and its later consequences, with utero-placental ischemia by uterine artery ligation (UAL) being the most frequently used in rats. The relevance of this model lies in the fact that it induces altered placental perfusion, the main cause of IUGR in humans in Western countries. However, there is also controversy over the grade and homogeneity of IUGR obtained. In this study, we propose a new animal model of IUGR related to placental ischemia through the cauterization of meso-ovarian vessels. We aimed to test the feasibility of meso-ovarian vessel cauterization (CMO), and to compare it with uterine artery ligation (UAL). The CMO group had similar incidence of perinatal mortality, percentage of IUGR, and evolution of body weight during early extrauterine life to the UAL group, indicating that both methods are similarly efficient for inducing IUGR. Moreover, both of them affect the ratio of fetal to placental weight, and the weight of vital organs, supporting the hypothesis of a fetal compensatory response or "brain- and heart-sparing effect". Both operative models suffer approximately 50% perinatal mortality, implying that they are both more efficient in the production of IUGR when C-section is performed. On the other hand, CMO was significantly faster to perform than UAL and seemed to produce a more uniform ischemia throughout the uterus than the UAL method, resulting in a more homogeneous group of IUGR pups.
Placenta 2009 Sep
PMID:Cauterization of meso-ovarian vessels, a new model of intrauterine growth restriction in rats. 1963 78

Preeclampsia is a complex disease of pregnancy with both feto-placental and maternal factors contributing to its pathogenesis. Failed transformation of the uterine spiral arteries leading to release of ischemic placental factors into the maternal circulation is thought to be the initial step in triggering preeclampsia. One placental factor associated with preeclampsia is necrotic trophoblastic debris that is deported in the maternal blood. The deported material ranges from multinucleated syncytial knots to nano-meter scale exosomes. Increasingly, it is being questioned whether failed transformation of the spiral arteries with subsequent placental ischemia is either necessary, or adequate, to explain the genesis of preeclampsia. In clinically established preeclampsia, maternal circulating levels of cytokines, such as TGFbeta, IL-6 and TNFalpha, are reported to be elevated. This study investigates whether cytokines can increase the shedding of necrotic material from the placenta. To investigate this question, placental explants were treated with nine cytokines which resulted in significantly increased amounts of trophoblasts being shed from explants treated with IL-6, TGFbeta-1 or TNFalpha but not the other cytokines. Trophoblasts shed from explants treated with IL-6, or TGFbeta-1 demonstrated a significant reduction in the activities of caspases while exposing endothelial cells to trophoblasts shed from explants treated with IL-6, TGF beta1 or TNFalpha resulted in endothelial cell activation. These results suggest that some cytokines can induce excess and/or aberrant death (necrotic or aponecrotic) trophoblast death. If reflected in vivo this might explain, at least in part, how some cytokines could affect trophoblast shedding/deportation and contribute to the pathogenesis of preeclampsia.
Placenta 2010 Jan
PMID:IL-6, TNFalpha and TGFbeta promote nonapoptotic trophoblast deportation and subsequently causes endothelial cell activation. 1994 58

During the first trimester of pregnancy the human placenta develops in an hypoxic environment caused by the occlusion of uterine spiral arterioles by extravillous trophoblasts (EVT). This period of low oxygen tension is crucial for successful pregnancy. In low oxygen environments, Hypoxia Inducible Factors (HIF) are the main regulators in the transcription of a number of genes. Target genes can induce anaerobic processes, reducing oxygen consumption, or promote angiogenesis, which establishes and enhances the vascular environment. The HIFs can function throughout all stages of placental differentiation and growth both in normal and pathological pregnancies (compromised by hypoxia/ischemia). Interestingly, HIFs respond to a multitude of changes during pregnancy, including 1) low oxygen, 2) renin-angiotensin system (RAS), 3) cytokines, and 4) growth factors, all of which regulate placental function. This review explores oxygen-dependent and oxygen-independent regulation and the role of HIF in placental development and differentiation.
Placenta 2010 Nov
PMID:Regulation of hypoxia inducible factors (HIF) in hypoxia and normoxia during placental development. 2086 70


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