Autacoid interactions in the regulation of blood flow in the human placenta

1. Interactions between autacoids may play important roles in the regulation of blood flow in the foetal placenta. In order to investigate this aspect of placental haemodynamics, human normal-term placentae were perfused in vitro and the responses of the foetal vessels to various combinations of vasoactive agents were determined. 2. Vasoconstriction responses to 5-hydroxytryptamine (5-HT) were potentiated in the presence of endothelin-1 (ET-1), the thromboxane A2-mimetic U46619 and a nitric oxide synthase inhibitor, N-nitro-L-arginine (NOLA), but not in the presence of angiotensin II. 3. N-Nitro-L-arginine caused vasoconstriction of the perfused placenta and indomethacin attenuated this effect and blocked the potentiation of the 5-HT response by NOLA. 4. Indomethacin did not affect ET-1-induced pressure increases and infusion of U46619 had no effect on release of ET-like immunoreactivity into the foetal placental circulation. 5. The present study provides evidence of interactions between several autacoids in human perfused placentae in vitro. These interactions may play important roles in foetal placental haemodynamics in normal or pathological situations.     

Inhibition of feline collateral vessel development following experimental thrombolic occlusion

We compared development of feline hindlimb collateral circulation after acute occlusion of the terminal aorta by ligation, thrombus formation, and formation of a "closed" aortic loop containing thromboplastin. Collateral circulation development was assessed by aortograms, scintillation scans, neurological signs following occlusion, measurement of hindlimb muscle blood flow, and forelimb and hindlimb temperature. In cats in which aortic occlusion was the result of ligation or thromboplastin in the aortic loop, paralysis was not evident. Aortograms and scintillation scans indicated hindlimb blood flow. Both muscle temperature and blood flow data indicated that the return of blood flow was rapid. The 5th lumbar artery appears to be the origin of the collateral vessels. The mid-zone component is a dorsal and ventral vertebral route and an epaxial muscle route. The reentry components are the 6th or 7th lumbar arteries. The collateral vessels arise from preexisting collateral vessels. Of those cats in which aortic occlusion was the result of a thrombus, all exhibited paralysis. Aortograms, scintillation scans, muscle temperature, and hindlimb blood flow data indicated reduced hindlimb blood flow. The results suggest that the thrombus has an inhibitory effect on the development of collateral circulation.     

Transvaginal color Doppler in early pregnancy: rational and clinical potential

Remarkable hemodynamics changes that occur in the maternal circulation, the continuous growth and development of the feto-placental circulation is now studied by transvaginal Doppler. This seems to give more light in understanding of the early pregnancy pathophysiology. For the first time, it seems that ultrasound might be able to distinguish different forms of gestational trophoblastic disease. Due to its non-invasiveness and relatively simple and easily performed technique, transvaginal color Doppler might be of considerable clinical value. The other important point is that study results are available immediately for clinical judgement. From our study, we can conclude that transvaginal ultrasound with color and pulsed Doppler is potentially valuable diagnostic tool to differentiate forms of the gestational trophoblastic diseases. On the basis of Doppler findings, the complete mole can be reliably distinguish from the invasive mole or choriocarcinoma. The degree of myometrial invasion can be also assessed. This can be an objective foundation for therapeutical approach. There is no doubt that studies of maternal-fetal circulation in early pregnancy may help for better understanding of physiological and pathophysiological hemodynamic changes. Investigation of maternal (main uterine, arcuate, radial and spiral) arteries; placental (umbilical, chorionic arterioles) vessels and fetal (aorta and intracranial circulation) arteries flow patterns may help in order to diagnose abnormal implantation. More studies are necessary in order the Doppler technique to be used for clinical judgment in early pregnancy. Safety aspects should also be considered. However, potentials of these technique are more then obvious.     

MRI of intramedullary sarcoidosis: follow-up of a case

Significative enhancement of free radical formation (FRO) in vivo is an important feature of hypertensive disorders of pregnancy (HDP), namely preeclampsia (PIH). The latest investigations about the pathology of HDP, showed the contribution of placental circulation to the development and evolution of such disease. The placental bed can be a potential source of FRO or activation of cells that can produce FRO. Glutathione, is an important molecule for cellular protection against damage, is a cofactor of many enzymes, in particular, for the glutathione peroxidase of the placental tissue; this enzyme in the placenta bed prevent the production of thromboxan and lipoperoxides; the latter are potentially damaging to the endothelium cells and can cause vasoconstriction, the most important feature of PIH. The activity of that enzyme is deficient in PIH. We studied, by fluorometric assay, the concentrations of the two states of glutathione in placental homogenates (PLH) from pregnant women without pathology (PWN) and from pregnant women with PIH (PWPIH). The data showed significant low concentrations in the PLH of the two states of glutathione in the PWN against high concentrations of this molecule in the PLH from PWPIH. This feature can result from a deficient user of the glutathione by the cellular mechanism for prevention against oxidative factors. In addition, our study shows a biochemical marker that is suggestive that the placental bed is a potential source of FRO production in PIH.     

Primary pulmonary hypertension in adults]

Primary pulmonary hypertension is a rare disease of unknown etiology which relates to the precapillary form of the hypertension. The review of the literature and authors' data on the changes of pulmonary vessels and the heart weight are presented. So-called plexiform structure characteristics for this pathology are considered by the authors as glomus anastomoses developing as a compensation of pulmonary circulation disturbances.     

Placental villous stroma as a model system for myofibroblast differentiation

Different subtypes of myofibroblasts have been described according to their cytoskeletal protein patterns. It is quite likely that these different subtypes represent distinct steps of differentiation. We propose the human placental stem villi as a particularly suitable model to study this differentiation process. During the course of pregnancy, different types of placental villi develop by differentiation of the mesenchymal stroma surrounding the fetal blood vessels. In order to characterise the differentiation of placental stromal cells in the human placenta, the expression patterns of the cytoskeletal proteins vimentin, desmin, alpha- and gamma-smooth muscle actin, pan-actin, smooth muscle myosin, and the monoclonal antibody GB 42, a marker of myofibroblasts, were investigated on placental tissue of different gestational age (7th-40th week of gestation). Proliferation patterns were assessed with the proliferation markers MIB 1 and PCNA. Additionally, dipeptidyl peptidase IV distribution was studied in term placenta and the ultrastructure of placental stromal cells was assessed by electron microscopy. Different subpopulations of extravascular stromal cells were distinguished according to typical co-expression patterns of cytoskeletal proteins. Around the fetal stem vessels in term placental villi they were arranged as concentric layers with increasing stage of differentiation. A variable layer of extravascular stromal cells lying beneath the trophoblast expressed vimentin (V) or vimentin and desmin (VD). They were mitotically active. The next layer co-expressed vimentin, desmin, and alpha-smooth muscle actin (VDA). More centrally towards the fetal vessels, extravascular stromal cells co-expressed vimentin, desmin, alpha- and gamma-smooth muscle actin, and GB 42 (VDAG). Cells close to the fetal vessels additionally co-expressed smooth muscle myosin (VDAGM). Ultrastructurally, V cells resembled typical mesenchymal cells. VD cells corresponded to fibroblasts, while VDA and VDAG cells developed features of myofibroblasts. Cells of the VDAGM-type revealed a smooth muscle cell-related ultrastructure. In earlier stages of pregnancy, stromal cell types with less complex expression patterns prevailed. The media smooth muscle cells of the fetal vessels showed a mixture of different co-expression patterns. These cells were separated from extravascular stromal cells by a layer of collagen fibres. The results obtained indicate a clearly defined spatial differentiation gradient with increasing cytoskeletal complexity in human placental stromal cells from the superficial trophoblast towards the blood vessels in the centre of the stem villi. The spatial distribution of the various stages of differentiation suggests that human placental villi could be a useful model for the study of the differentiation of myofibroblasts.     

Possible effects of placental leucine aminopeptidase on the regulation of brain-gut hormones in the fetoplacental unit

The hydrolysis of somatostatin by human placental subcellular fractions and pregnancy sera was studied in the presence of selective inhibitors and the antibody against pregnancy serum oxytocinase (placental leucine aminopeptidase; EC3.4.11.3) by measuring the released amino acids by high-performance liquid chromatography. We also studied the degradation of other brain-gut hormones, such as glucagon, growth hormone, growth hormone releasing factor, and insulin, in the human placenta and found that the human placenta degrades somatostatin, glucagon, and growth hormone releasing factor, but not insulin and growth hormone. The degradation velocity of somatostatin was ten times greater than that of growth hormone releasing factor in placental microsomal fractions. Our data suggest that the stimulatory control by growth hormone releasing factor is dominant in the fetal growth hormone secretion. Our data also identified the somatostatin-degrading protease in human placenta using placental leucine aminopeptidase. It is known that the mean somatostatin levels in the umbilical artery are about 2.5-fold higher than those in the umbilical vein. Our data on somatostatin levels in umbilical artery and vein of intrauterine growth retardation human fetuses showed that the ratio umbilical artery/vein is around 1. Since insulin is known to be the primary hormone regulating the ratio of fetal growth, our data suggest that the degradation of somatostatin in the placenta is decreased and that elongation of somatostatin effects may result in the inhibition of insulin secretion in the intrauterine growth retardation fetus.     

Pulmonary veins and bronchial vessels undergo remodeling in sustained pulmonary hypertension induced by continuous air embolization into sheep

While it is well known that chronic pulmonary hypertension is accompanied by characteristic structural changes in the pulmonary arteries, it is becoming increasingly apparent that the remodeling process also involves the venous side of the circulation. The present paper utilizes a sheep model of sustained pulmonary hypertension induced by continuous air embolization (CAE) into the pulmonary arterial circulation to examine the structure of the pulmonary veins and bronchial vasculature. Morphometric techniques were applied to the pulmonary veins and bronchial vessels following distension of the venous circulation with a barium-sulfate gelatin mixture; this route of filling also resulted in distension of the bronchial vessels. Four and 12 days of CAE resulted in a significant increase in the proportion of muscular pulmonary veins (e.g., percent muscular veins < 75 microns following 12 days CAE = 17.7 +/- 6.9; controls = 0), an approximate doubling in percent venous medial thickness, and a 50% reduction in number of barium-filled peripheral vessels. Examination of the bronchial circulation revealed a striking increase in volume due both to a 50% increase in vessel diameter and a threefold increase in number of small vessels (p < .05). The authors conclude that CAE-induced chronic pulmonary hypertension is associated with remodeling of both the pulmonary veins and bronchial circulation as well as the pulmonary arteries. The mechanisms for these structural alterations are not certain, but may include local release of vasoactive and inflammatory mediators and an increase in bronchopulmonary anastomoses.     

The effect of intravenous immunoglobulin on placental transfer of a platelet-specific antibody: anti-P1A1

The isolated perfused lobule of human placenta was used as an in-vitro model to study the effect of intravenous immunoglobulin (IVGG) on the placental transfer of a human platelet-specific antibody (anti-P1A1). Normal human IgG was shown to transfer from the maternal to the fetal circulation of the placental model after a lag period of 2-3 h. IVGG also transferred across the placenta but only after a longer lag period (3-4 h) than normal human IgG at the same concentration, which suggests that IVGG may contain a factor that inhibits the transfer of its own component IgG. The sensitive Western immunoblotting technique was used to demonstrate progressive transfer of anti-P1A1 antibody to the fetal circulation after a 2-3 h lag period. When IVGG and anti-P1A1 antibody were added simultaneously to the maternal circulation, the transfer of platelet-specific antibody was strongly inhibited by IVGG. The inhibitory effect of IVGG on anti-P1A1 antibody transfer was consistent for three different batches of the same IVGG product (Sandoglobulin). These studies provide the first scientific data to support the use of IVGG to inhibit antiplatelet antibody transfer as part of the antenatal management of neonatal alloimmune thrombocytopenia.     

Embryonal morphogenesis of the intraorgan circulatory bed, lymphatic outflow pathways and innervation structures

Development of the circulation bed in human embryogenesis is brought about by a loop-like growth of vessels manifesting in proliferation, integration and morphofunctional transformation of the vascular loops. Proliferation of the loops ensures the blood inflow and reflux at all levels while their integration is followed by formation of hemocirculation system with appearance of the connective and major capillaries which serve the basis for development of true capillaries and capillary network in which precapillary arterioles and postcapillary venules can be distinguished. Hemocirculation system is completed by formation of the arteriolar and venular collaterals and arteriolo-venular anastomoses. Non-participation in the angiogenesis of the autogenic vessel endotheliocytes and their widespread necrosis give grounds to suggest that they are genetically condemned to death. Development of lymph vessels and innervation occurs simultaneously and together with blood vessels by mechanism of their centrifugal growth.     

Monitoring aortocoronary bypass. A new experimental approach

Only few data are known concerning haemodynamic parameters and pathomechanisms of small vessels and bypass grafts. No easy-to-use bedside method exists for monitoring. We developed a miniaturised implantable Doppler probe linked to a 20 MHz pulsed Doppler system. In a circulation model and in animal studies we can show the accuracy of this method. We conclude that the implantable pulsed Doppler system is a sensitive method for monitoring the haemodynamics of small vessels.     

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus

OBJECTIVE: Results from several recent studies suggest that the levels of antigenic keratan sulfate (agKS) and hyaluronan (HA) in serum provide useful information about changes taking place in injured or diseased synovial joints. To improve our understanding of the significance of such changes, we investigated the points of entry of these molecules into the blood circulation and their subsequent clearance after experimentally induced injury to rabbit knee joint. METHODS: Chymopapain was injected into knee joints of 8 young adult rabbits to induce aggrecan degradation in articular cartilage within the injected joint. Levels of agKS and HA in serum from various blood vessels were measured before and 5 h after the injury. The statistical significance of injury related changes and differences among the different vessels were evaluated. RESULTS: After the injury, the level of agKS rose most significantly in the popliteal vein draining the injected knee joint and dropped rapidly by the time the blood reached the femoral vein. The level of agKS was similar, although lower, in other blood vessels but, in each case, it was significantly higher than before the injection. The level of HA showed a different pattern of changes after injection. While highest in the popliteal vein draining the injected knee, HA was markedly elevated in the cranial vena cava, close to the entry of lymph into the circulation, and was 50% lower in the hepatic than in the portal vein. CONCLUSION: (1) Measurement of agKS and HA in a blood vessel draining or close to an injured/diseased knee joint may provide more specific information about degradative changes taking place in that joint than measurement of levels of these markers in other blood vessels; (2) some HA molecules but no measurable amounts of agKS enter the blood circulation via the lymphatic system: and (3) HA but not agKS is very rapidly cleared from the blood by the liver.     

Spatiotemporal expression of C-CAM in the rat placenta

We investigated the expression of the immunoglobulin superfamily cell adhesion molecule, C-CAM, in developing and mature rat placenta. By immunohistochemical staining at the light microscopic level, no C-CAM-expression was seen before Day 9 of gestation, when it appeared in the trophoblasts of ectoplacental cones. On Day 10.5, spongiotrophoblasts and invasive trophoblasts around the maternal vessels of the decidua basalis were stained positively. On Day 12.5, C-CAM was detected in the spongiotrophoblasts of the junctional layer, but labyrinth trophoblasts and secondary giant trophoblasts were not stained. On Day 17.5, C-CAM was found only in the labyrinth and lacunae of the junctional layer. At this stage, both the labyrinth cytotrophoblasts of the maternal blood vessels and the endothelial cells of the embryonic capillaries were strongly stained. Placental tissues from gestational Days 12.5 and 17.5 were analyzed by immunoelectron microscopy to determine the location of C-CAM at the subcellular level. On Day 12.5, positive staining of the spongiotrophoblasts was observed, mainly on surface membranes and microvilli between loosely associated cells. On Day 17.5, staining was found primarily on the microvilli of the maternal luminal surfaces of the labyrinth cytotrophoblasts, and both on the luminal surface and in the cytoplasm of endothelial cells of the embryonic vessels. RT-PCR analysis and Southern blotting of the PCR products revealed expression of mRNA species for both of the major isoforms, C-CAM1 and C-CAM2. Immunoblotting analysis of C-CAM isolated from 12.5-day and 14.5-day placentae showed that it appeared as a broad band with an apparent molecular mass of 110-170 kD. In summary, C-CAM was strongly expressed in a specific spatiotemporal pattern in trophoblasts actively involved in formation of the placental tissue, suggesting an important role in placental development. In the mature placenta, C-CAM expression was confined to the trophoblastic and endothelial cells lining the maternal and embryonic vessels, respectively, suggesting important functions in placental physiology.     

Haemodynamic model of twin-twin transfusion syndrome in monochorionic twin pregnancies

Twin-twin transfusion syndrome in monochorionic twin pregnancies is not understood completely and is controversial which hampers development of acceptable diagnostic and rational treatment strategies. A haemodynamic model was developed that relates fetal growth with (1) fetoplacental blood flow and fetomaternal effects, and (2) net twin-twin transfusion from donor to recipient twin. Fluid balance mechanisms were neglected. Placental vascular anastomoses (arteriovenous, venoarterial, arterioarterial, venovenous) were modelled as straight blood vessels connecting the placental cord insertions that grow during pregnancy. Poiseuille's law predicts significantly decreasing anastomosing resistances, and when placental sharing is unequal it is assumed that smaller placental fractions cause smaller blood volumes and pressures. Two coupled first-order differential equations describing each twin's blood volume were determined and analysis showed that placental and anastomotic development cause anastomotic blood flow to increase faster than fetal growth. Hence, it is proposed as the syndrome's underlying pathophysiology that fetal discordance increases progressively, beyond fetal compensatory capacity. Fewer anastomoses cause larger discordance, but its onset can vary widely during pregnancy. Arteriovenous plus compensating anastomoses produce dynamic steady-state growth patterns with large, opposite, measurable anastomotic blood flows. Clinical study of fetal growth patterns may identify the syndrome's underlying placental anatomy. Predicted trends depend only weakly on implemented fetal physiology and are most likely realistic. This knowledge could improve future management of the syndrome.     

Numerical Simulation of Fluxes Generated by Inhomogeneities of the Underlying Surface over the Jinta Oasis in Northwestern China

Using land-use types derived from satellite remote sensing data collected by the EOS Moderate Resolution Imaging Spectroradiometer (EOS/MODIS),the mesoscale and turbulent fluxes generated by inhomogeneities of the underlying surface over the Jinta Oasis,northwestern China,were simulated using the Regional Atmospheric Modeling System (RAMS4.4).The results indicate that mesoscale circulation generated by land-surface inhomogeneities over the Jinta Oasis is more important than turbulence.Vertical heat fluxes and water vapor are transported to higher levels by mesoscale circulation.Mesoscale circulation also produces mesoscale synoptic systems and prevents water vapor over the oasis from running off.Mesoscale circulation transports moisture to higher atmospheric levels as the land-surface moisture over the oasis increases,favoring the formation of clouds,which sometimes leads to rainfall.Large-scale wind speed has a significant impact on mesoscale heat fluxes.During the active phase of mesoscale circulation,the stronger large-scale winds are associated with small mesoscale fluxes; however,background wind seems to intensify the turbulent sensible heat flux and turbulent latent heat flux.If the area of oasis is enlarged properly,mesoscale circulation will be able to transport moisture to higher levels,favoring the formation of rainfall in the oasis and protecting its "cold island" effect.The impact of irrigation on rainfall is important,and increasing irrigation across the oasis is necessary to protect the oasis.     

Placental agenesis, embryonal hydraemia, embryolethality and acute hypervitaminosis A in rats

Acute maternal hypervitaminosis A established on Day 9 of gestation in Sprague-Dawley-derived rats caused a dose-related increase in the resorption of implants. The median embryolethal dose was 189,000 i.u./kg. In addition to suppression of the allantois leading to placental agenesis, damaged embryos showed retarded somatic development and hydraemia, all apparent 24 h after treatment. At about Day 11 the hydraemia involved the visceral wall of the yolk sac causing death of the embryo soon after. The fluid in the vitelline vessels continued to collect until Day 13 when it absorbed following necrosis of the wall of the yolk sac. Two mechanisms are suggested for the embryonal hydraemia: either the excess fluid resulted from a permeability disorder induced by the vitamin A; or it was retained metabolic water or water specifically absorbed to inflate the allantois and, being unused for this purpose, it pooled in the blood vessels of the embryo. The yolk sac hydraemia is more likely to have followed injury to the proximal endoderm.     

Laser-assisted microvascular anastomosis of human adult and placental arteries with expanded polytetrafluoroethylene microconduit

Laser-assisted microvascular anastomoses can be performed more quickly than sutured anastomoses, yet manifest similar patency rates and tensile strength. This study was undertaken to determine if in vitro laser-assisted microvascular anastomoses could be created between human adult arteries (anterior tibial arteries), human placental arteries, and expanded polytetrafluoroethylene microconduits. A CO2 laser was applied in single or continuous bursts with a matrix of variables encompassing power P = 80 to 160 mW, spot size SS = 150 to 500 microns, and exposure time EXP = 1.0-second continuous exposure (n = 2 each composite setting). The endpoints measured to assess the ability to laser-weld vessels were morphologic appearance by scanning electron microscopy and bursting strength. Scanning electron microscopy revealed apparent fusion of human placental arteries and human adult arteries to expanded polytetrafluoroethylene microconduits at settings of P = 130 mW, SS = 300 microns, and EXP = 1.0 second, though bursting pressure at all settings was less than 10 mmHg. Laser-assisted microvascular anastomoses of human placental artery to human placental artery and human adult artery to human adult artery were successful at this setting, though bursting pressures of anastomoses incorporating placental vessels were significantly weaker than those created with adult tissue. The relative weakness of laser-assisted microvascular anastomoses incorporating placental arteries might be explained by qualitative or quantitative differences in vessel wall collagen, as seen in fetal tissue, and deserves further characterization.     

Prostaglandin E2 in human placenta: its vascular effects and activation of prostaglandin E2 formation by nicotine and cotinine

Tobacco smoking by pregnant women increases the frequency of spontaneous abortions and preterm births. Human labor is associated with enhanced intrauterine phospholipid metabolism and production of prostaglandin E2 (PGE2) which induces labor, initiates uterine contractions and maintains the homeostasis of placental blood flow. Therefore, we studied: (a) the influence of nicotine and cotinine on the effects of PGE2 on placental vasculature in perfused human placental cotyledon, and (b) the activation of placental phospholipase A2 (PLA2) by nicotine and cotinine using 1-palmitoyl-2-[1-14C]arachidonyl-phosphatidylethanolamine (PE, 2.2 nmol) as substrate. These studies revealed that: (1) increasing concentrations of PGE2 (10- 150 ng/ml) increased umbilical perfusion pressure by 170 +/- 10% (n = 6) of control (100%). Cotinine (2 microg/ml) enhanced this effect at all concentrations of PGE2. Nicotine (2 microg/ml) prevented the effect of PGE2; (2) both cotinine (EC50 470-500 fmol/l) and nicotine (EC50 18-32 pmol/l) activated PLA2 in human placental tissues. These observations indicated that cotinine was more potent than in nicotine activating PLA2 and potentiating the vasoconstrictive effects of PGE2 on fetal placental circulation. Nicotine activates nicotinic receptors and releases placental acetylcholine, a vasodilator of placental arteries. Acetylcholine stimulates muscarinic receptors of endothelial cells resulting in the release of endothelium-derived relaxing factor (EDRF), and possibly nitric oxide. Therefore, nicotine prevents or abolishes the vasoconstrictive effects of PGE2 through the release of EDRF. Cotinine is inactive at nicotinic and muscarinic receptors. Therefore, accumulation of cotinine, the major metabolite of nicotine, in fetal circulation may contribute to production of PGE2 and induction of preterm labor and spontaneous abortions.     

Presence of the pineal hormone melatonin in rat cochlea: its variations with lighting conditions

Within the normal inner ear, there are elements that belong to the immune system. Different inner ear disorders can be explained by autoimmune mechanisms, affecting both humoral and cellular immunity. Melatonin, the principal hormone of the pineal gland, modulates the immune system and extensively participates in the autoimmune processes related to type II collagen. Therefore, we have studied the presence of melatonin in rat cochlea, proving that its concentrations change depending on lighting conditions. Rats show high levels when confined to darkness and low levels when subject to continuous light exposure. The results correlate with the concentration of melatonin in peripheral circulation. Further experimental and clinical studies are necessary to clarify the role and the possible therapeutic applications of melatonin.