Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unknown. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion. Placental ischemia/hypoxia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium, vasoconstriction and hypertension. Experimental induction of chronic uteroplacental ischemia appears to be the most promising animal model to study potential mechanisms of preeclampsia since reductions in uteroplacental blood flow in a variety of animal models lead to a hypertensive state that closely resembles preeclampsia in women. This chapter details the methods we use in our laboratory to produce the reduced uterine perfusion pressure (RUPP) model in the pregnant rat.
 ...
PMID:Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. 1651 95

New, critically important data have been recently generated about the response to hypoxia. This response can be schematized in three main systems or functions, ie, detectional or oxygen sensing, regulatory, which controls gene expression and effector. The principal organizer of the regulatory branch is a specific transcription factor, the hypoxia-inducible factor 1 (HIF-1). In the presence of oxygen, the alpha subunit of HIF-1 (HIF-1alpha) is modified by hydroxylases, that represent the central point of the oxygen sensing mechanism. This type of hydroxylation induces HIF-1alpha catabolism by the proteosome. On the contrary, in hypoxia, or in the presence of certain growth factors that increase HIF-1alpha synthesis, HIF-1alpha translocates to the nucleus, where it binds HIF-1beta, and thence acts on transcription of genes carrying hypoxia responsive elements (HRE) on their promoters. These genes regulate the synthesis of an ample series of proteins, which span from respiratory enzymes and transporters to hormones regulating circulation and erythropoiesis. The role of HIF-1alpha is not restricted to the mere induction of adaptation to decreased oxygen: instead, it significantly participates in cell repairing mechanisms. A simple list of some of the stimulatory or inhibitory alterations of pathophysiological importance involving the HIF-1 system, would include: chronic lung disease, smoking adaptation, anemia/hemorrhage, ischemia/reperfusion, growth, vascularization and cell resistance of tumors, preeclampsia and intrauterine growth retardation, retinal hyper o hypovascularization, drug intoxications, bowel inflammatory disease and wound repair. This list illustrates by itself the importance of the mechanism herein reviewed.
 ...
PMID:[Response to hypoxia. A systemic mechanism based on the control of gene expression]. 1671 69

Normal pregnancy is associated with significant changes in the neuronal and vascular control mechanisms of blood pressure (BP). Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria, and increased vascular resistance and BP. If untreated, PE leads to eclampsia with serious seizures and severe hypertension. However, the neurovascular mechanisms of hypertension in pregnancy and PE are unclear. Studies in animal models of hypertension in pregnancy suggest that inadequate cytotrophoblast invasion of uterine spiral arteries causes reduction in uteroplacental perfusion pressure leading to placental ischemia/hypoxia. Placental ischemia may promote the release of biologically active factors such as cytokines and reactive oxygen species. These circulating factors may increase the vascular permeability, cross the blood-brain barrier, and affect the sympathetic tone and the neuronal control mechanisms of BP. Placental factors could also cause endothelial cell dysfunction and inhibit nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), prostacyclin (PGI(2))-cyclic adenosine monophosphate (cAMP), and hyperpolarizing factor vascular relaxation pathways. Additionally, placental factors may induce endothelium-derived contracting factors such as endothelin, thromboxane and angiotensin II, which stimulate Ca(2+)-dependent vascular smooth muscle (VSM) contraction or increase protein kinase C activity and enhance myofilament sensitivity to intracellular free calcium concentration ([Ca(2+)](i)). The increased sympathetic tone combined with systemic decrease in endothelium-dependent vascular relaxation and enhanced VSM contraction may contribute to the increased vascular resistance and BP associated with PE. The hypertensive state in severe PE may weaken the blood-brain barrier and precipitate convulsions and cerebral hemorrhage. Careful monitoring of maternal neuronal, endothelial, and VSM function during pregnancy should circumvent the life-threatening neurovascular complications of PE-eclampsia.
 ...
PMID:Neurovascular mechanisms of hypertension in pregnancy. 1671 96

Pre-eclampsia or pregnancy induced hypertension (PIH) affects 6-8% of all pregnancies. Although the underlying mechanism of PIH is still unknown, it is widely believed that the placenta plays an important role. It was thought that an ischemic placenta due to poor perfusion can precipitate the signs and symptoms of PIH. This study aims to investigate the possible role of Type 1(AT1) and Type 2 (AT2) angiotensin II receptor subtypes in the mechanism of PIH. AT1 receptor stimulation causes vasoconstriction and AT2 receptor stimulation causes vasodilatation. Investigating the interactions of these two receptors in the placenta provides an insight as to the balance that may exist between AT1 and AT2 receptors in normal pregnancy. Any disruption to the balance might cause a disruption of the blood flow in the placenta, leading to PIH. Placentas were collected from 11 PIH patients and 11 normal patients. Immunohistochemistry techniques were performed on the placental tissue to determine the distribution of AT1 and AT2 receptors in the placental tissue qualitatively and quantitatively. It was observed that in normal patients, the balance between AT1 and AT2 receptors is that the level of AT2 receptors is higher than the level of AT1 receptors. However in the PIH patient, it was observed that the normal balance was disrupted. In PIH patients the level of AT1 receptors was observed to be higher than the level of AT2 receptors. This study suggests that disruption of the balance between AT1 and AT2 receptors observed in PIH placentas might cause a decrease in blood flow to the placenta, causing it to be poorly perfused. This may cause placental ischemia which may lead to PIH.
 ...
PMID:A preliminary finding: immunohistochemical localisation and distribution of placental angiotensin II receptor subtypes in normal and preeclamptic pregnancies. 1689 8

Pre-eclampsia, a hypertensive disorder of pregnancy, affects 5 to 7% of pregnancies. Oxidative stress-induced placental injury and subsequent release of placental debris into the maternal circulation are key pathogenic events in the progression of pre-eclampsia. Women who smoke cigarettes throughout pregnancy are 33% less likely to develop this disorder than nonsmoking women. We postulated that elevated carbon monoxide concentrations in serum of smoking women inhibits apoptosis and debris shedding of trophoblast cells exposed to ischemia-reperfusion injury because carbon monoxide has cytoprotective effects on endothelial and smooth muscle cells in culture. This may be responsible for the reduced risk of pre-eclampsia in smoking women. To assess the cytoprotective properties of carbon monoxide within placental tissue, carbon monoxide treatments were administered to in vitro hypoxia/reoxygenation-insulted villous explants cultured from term human placenta. Induction of apoptosis was assessed using molecular and morphological approaches. Placental villous explants treated with carbon monoxide demonstrated 60% less hypoxia/reoxygenation-induced apoptosis in the differentiated syncytiotrophoblast layer compared with untreated explants undergoing a similar insult. In addition, retention of intact syncytial membranes was observed in carbon monoxide-treated explants. These observations indicate that carbon monoxide has potent antiapoptotic properties within human placenta and may hold therapeutic potential in the treatment of pre-eclampsia.
 ...
PMID:Carbon monoxide inhibits hypoxia/reoxygenation-induced apoptosis and secondary necrosis in syncytiotrophoblast. 1693 54

Reduced perfusion to the placenta in early pregnancy is believed to be the initiating factor in the development of preeclampsia, triggering local ischemia and systemic vascular hyperresponsiveness. This sequence of events creates a predisposition to the development of altered vascular function and hypertension. This study was designed to determine the influence of placental insufficiency on the responsiveness of mesenteric resistance arteries in an animal model of preeclampsia. Placental insufficiency was induced by reduction in uteroplacental perfusion pressure (RUPP) in experimental Sprague-Dawley rat dams. The uterine branches of the ovarian arteries and the abdominal aortae of pregnant rats were surgically constricted on gestational Day 14. Dams in the control group underwent a sham procedure. Rats were euthanized on gestational Day 20, followed by removal of the small intestine and adjacent mesentery. First-order mesenteric resistance arteries were mounted on a small vessel wire myograph and challenged with incremental concentrations of vasoconstrictors and vasorelaxants. Mesenteric arteries in dams with placental insufficiency demonstrated an increased maximal tension to phenylephrine (7.15 +/- 0.15 vs. 5.4 +/- 0.27 mN/mm, P < 0.001); potassium chloride at 60 mM (3.43 +/- 0.11 vs. 2.77 +/- 0.14 mN/mm, P < 0.01) and 120 mM (3.92 +/- 0.18 vs. 2.97 +/- 0.16 mN/mm, P < 0.01); and angiotensin II (2.59 +/- 0.42 vs. 1.51 +/- 0.22 mN/mm, P < 0.05). Maximal relaxation to endothelium-dependent relaxants acetylcholine and calcium ionophore (A23187) was not significantly reduced. Data suggest that placental insufficiency leads to hyperresponsiveness to vasoconstrictor stimuli in mesenteric arteries.
 ...
PMID:Mesenteric vascular responsiveness in a rat model of pregnancy-induced hypertension. 1694 8

Damage of the placenta resulting from ischemia-reperfusion is important to the pathophysiology of preeclampsia. Here we investigated whether low concentrations of glyceryl trinitrate (GTN), a nitric oxide mimetic with anti-apoptotic properties, inhibit hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of chorionic villous explants from human placentas. Compared with villi analyzed immediately after delivery or maintained under normoxic conditions, villi exposed to a 6-hour cycle of hypoxia/reoxygenation exhibited greater numbers of syncytiotrophoblasts with terminal dUTP nick-end labeling (TUNEL)-positive nuclei in the syncytiotrophoblast. This increased number of TUNEL-positive nuclei was paralleled by higher levels of 4-hydroxynonenal (marker of lipid peroxidation), nitrotyrosine residues, and active caspase-3 and polyADP-ribose polymerase expression. Morphological analysis of explants exposed to hypoxia/reoxygenation revealed apoptotic and aponecrotic features similar to those of chorionic villi from preeclamptic pregnancies. Treatment with GTN during the hy-poxia/reoxygenation cycle blocked the increases in the number of TUNEL-positive nuclei and in the levels of 4-hydroxynonenal, nitrotyrosine, and active caspase-3. Incubation with GTN also attenuated the hypoxia/reoxygenation-induced polyADP-ribose polymerase expression and the apoptotic and aponecrotic morphological alterations. These results suggest that small concentrations of nitric oxide protect chorionic villi from hypoxia/reoxygenation-induced damage and provide a rationale for the use of low doses of nitric oxide mimetics in the treatment and/or prevention of preeclampsia.
 ...
PMID:Glyceryl trinitrate inhibits hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of the human placenta: therapeutic implications for preeclampsia. 1732 76

Preeclampsia is a complication of pregnancy with significant morbidity and mortality for the mother and the fetus. Presumptions are made that placental hypoxia has a causative role in the clinical syndrome. Furthermore, soluble fms-like tyrosine kinase 1 (sFLT-1) has been shown to have a role in the maternal syndrome of preeclampsia. We investigated the relationship between uteroplacental ischemia (UPI), the maternal clinical syndrome of preeclampsia and sFLT-1 in non-human primates. The induction of UPI in a pregnant non-human primate resulted in the development of a clinical entity analogous to human preeclampsia. This was illustrated by the increase in blood pressure, development of proteinuria, and renal histological changes identical to human preeclampsia. A significant elevation in the placental and peripheral blood mononuclear cell sFLT-1 mRNA expression was noted, translating to a significant elevation in circulating sFLT-1. Thus, this sequence suggests that a pathogenic reduction in placental perfusion results in the development of the maternal syndrome of preeclampsia and an increase in circulating sFLT-1, which is derived both from placental and extra-placental sources.
 ...
PMID:Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. 1749 34

We report a case of preeclampsia associated with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and concomitant nonbiliary acute pancreatitis and cholecystitis in the first postpartum day. A thorough investigation ruled out known etiologies of both pancreatitis and cholecystitis. Following conservative treatment, the patient's HELLP syndrome, pancreatitis, and cholecystitis resolved on the third postpartum day. Preeclampsia is associated with microvascular abnormalities that may involve the splanchnic circulation. These abnormalities may cause not only HELLP syndrome but also pancreatitis and cholecystitis. Recognizing that ischemia can damage not only the liver but also the pancreas and gallbladder, could result in improvements in the diagnosis and management of pancreatitis in patients with preeclampsia.
 ...
PMID:Acute pancreatitis and cholecystitis associated with postpartum HELLP syndrome: a case and review. 1745 15

Elevated circulating soluble fms-like tyrosine kinase 1 (sFLT-1) is associated with the development of the clinical signs and symptoms of preeclampsia. Placental ischemia has been suggested as one of the etiological factors that mediate increased sFLT-1 production in patients with preeclampsia, but definitive evidence for this hypothesis was lacking. Makris et al. demonstrate that inducing placental ischemia in primates is sufficient to induce sFLT-1 upregulation and the clinical signs and symptoms of preeclampsia.
 ...
PMID:Placental ischemia and soluble fms-like tyrosine kinase 1: cause or consequence of preeclampsia? 1737 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>