scholarly journals Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Shunping Gui ◽  
Shengping Zhou ◽  
Min Liu ◽  
Yanping Zhang ◽  
Linbo Gao ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Injury ◽  
Plasma Levels ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Potential Contribution ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Specific Syndrome

Preeclampsia (PE), a severe pregnancy-specific syndrome, is characterized by impaired placental angiogenesis. Although the pathogenesis of this condition remains largely unclear, vascular systemic endothelial injury is thought to be the common contributing factor. Soluble Axl (sAxl), a biomarker of endothelial dysfunction, is known to be abnormally increased in a variety of diseases associated with vascular injury. In a previous study, we found that the plasma levels of sAxl were significantly higher in PE with severe features (sPE) than in pregnant women who did not have PE. The current study aimed to further explore the potential role of sAxl in vascular injury in patients with sPE. We found that the upregulation of sAxl in maternal plasma was positively correlated with the plasma levels of sFlt-1 and negatively correlated with placental NO synthase (eNOS) in women with sPE. Furthermore, elevated levels of sAxl suppressed proliferation and endothelial tube formation and promoted cytotoxicity in human umbilical vein endothelial cells (HUVECs) through the downregulation of p-Akt, p-p70S6K, p-mTOR, and Grb2. Subsequently, we established a pregnant rat model with PE-like characteristics by injecting pregnant rats with an adenovirus expressing sAxl. These rats exhibited a typical PE-like phenotype, including increased blood pressure, proteinuria, and fetal growth restriction, along with abnormal placental and fetal renal morphology. In conclusion, our study demonstrated the role of sAxl in systemic vascular injury through the regulation of the expression of key molecules of angiogenesis and described its potential contribution to the development of sPE.

Carnitine in the Perinatal Metabolism of Lipids I. Relationship Between Maternal and Fetal Plasma Levels of Carnitine and Acylcarnitines

PEDIATRICS ◽  
1981 ◽  
Vol 67 (1) ◽  
pp. 95-100
Author(s):  
Milan Novak ◽  
Ellen F. Monkus ◽  
Dina Chung ◽  
Maria Buch
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Plasma Levels ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Free Carnitine ◽  
Acid Oxidation ◽  
Limited Capacity ◽  
Fetal Plasma ◽  
Arterial Plasma

Since premature infants have a limited capacity for fatty acid oxidation, supplementation with carnitine may improve their utilization of fat. Documentation of the source and extent of fetal carnitine reserves should explain the possible need for exogenous carnitine in the neonate. Correlation between free carnitine concentration in maternal and umbilical arterial plasma at birth (r = .45, P < .01) indicates that the initial concentration of free carnitine in the newborn depends on the maternal level. Thin-layer chromatography shows more γ-butyrobetaine in maternal than umbilical arterial plasma indicating higher availability of the precursor of carnitine biosynthesis. Elevated fatty acid oxidation in maternal tissues seems to be reflected by larger amounts of long-chain acylcarnitines in maternal plasma. Shortchain acylcarnitines, mainly acetylcarnitine, are higher in the umbilical vein than in maternal plasma (P < .01) indicating that the conceptus (the placenta or fetus) is either producing more or utilizing less acetylcarnitine. Plasma levels of carnitine rapidly decrease in premature newborns during the first three days after birth if no exogenous carnitine is given (P < .001), while no significant changes of total carnitine were detected in adult patients on total parenteral alimentation for one week. This difference indicates lower carnitine depots or limited capacity for carnitine biosynthesis in neonates. The possibility still requires further investigation that the development of the optimal rate of fatty acid oxidation in human newborns, as well as in other newborn mammals, may depend on the supply of exogenous carnitine.

1,25(OH)2D3 and Ca-binding protein in fetal rats: relationship to the maternal vitamin D status

1988 ◽  
Vol 254 (4) ◽  
pp. E505-E512 ◽  
Author(s):  
J. Verhaeghe ◽  
M. Thomasset ◽  
A. Brehier ◽  
F. A. Van Assche ◽  
R. Bouillon
Keyword(s):  
Vitamin D ◽  
Calcium Binding ◽  
Maternal Plasma ◽  
Diabetic Rats ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Fetal Plasma ◽  
Hormonal Function ◽  
Low Calcium ◽  
Calcium Phosphorus

The autonomy and functional role of fetal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] were investigated in nondiabetic and diabetic BB rats fed diets containing 0.85% calcium-0.7% phosphorus or 0.2% calcium and phosphorus and in semistarved rats on the low calcium-phosphorus diet. The changes in maternal and fetal plasma 1,25(OH)2D3 were similar: the levels were increased by calcium-phosphorus restriction and decreased by diabetes and semistarvation. Maternal and fetal 1,25(OH)2D3 levels were correlated (r = 0.80; P less than 0.001). The vitamin D-dependent calcium-binding proteins (CaBP9K and CaBP28K) were measured in multiple maternal and fetal tissues and in the placenta of nondiabetic, diabetic, and calcium-phosphorus-restricted rats. The distributions of CaBP9K and CaBP28K in the pregnant rat were similar to that of the growing rat. The increased maternal plasma 1,25(OH)2D3 levels in calcium-phosphorus-restricted rats were associated with higher duodenal CaBP9K and renal CaBPs, but placental CaBP9K was not different. In diabetic pregnant rats, duodenal CaBP9K tended to be lower, while renal CaBPs were normal; placental CaBP9K was decreased. No significant changes in CaBP levels were observed in fetuses of low calcium-phosphorus diet rats or fetuses of diabetic rats. The results indicate that in the rat fetal 1,25(OH)2D3 depends on maternal 1,25(OH)2D3 or on factors regulating maternal 1,25(OH)2D3. The lack of changes in fetal CaBP in the presence of altered fetal plasma 1,25(OH)2D3 levels confirms earlier data showing that 1,25(OH)2D3 has a limited hormonal function during perinatal development in the rat.

Gestational Age Dependency in the Prenatal Toxicity and in the Disposition Kinetics of the Novel Anticonvulsant HEPP (D,L-3-Hydroxy-3-ethyl-3-phenylpropionamide) after Subcutaneous Administration in Pregnant Rats

2007 ◽  
Vol 26 (3) ◽  
pp. 237-246 ◽  
Author(s):  
Lisbeth E. Gómez-Martínez
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Levels ◽  
Multiple Dose ◽  
Maternal Plasma ◽  
Maximum Plasma ◽  
Pregnant Rats ◽  
Fetal Period ◽  
Fetal Toxicity ◽  
Concentration Time

HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) is a novel anticonvulsant with promising anticonvulsant profile, which is being actively researched. The potential maternal and embryo/fetal toxicities of HEPP were evaluated in pregnant rats following subcutaneous (s.c.) administration during organogenesis (gestation days 6 through 14, GDs 6–14) and the fetal period (GDs 14–21). Single- and multiple-dose pharmacokinetics were also evaluated at the same periods in order to establish possible correlations with some maternal or embryo/fetal toxicity end points. Embryotoxicity was mainly indicated by a significant dose-concentration dependency in the increase in resorptions, high percentage of fully resorbed litters, and decrease in embryo body weights during the GD6–14 dosing period. No gross external alterations were observed in live fetuses. There was no indication of maternal toxicity; but a marked increase in maternal body weight was evident following dosing from GD14 to GD21. The maternal plasma profile following single subcutaneous dose of 50 mg/kg on both GD14 and GD21 showed a monoexponential elimination pattern. Statistically significant differences between treatments (GD14 versus GD21) were observed in elimination ( kel = 0.12 versus 0.15 h−1), absorption ( ka = 2.01 versus 3.14 h−1), maximum plasma concentration time points ( Tmax = 1.49 versus 1.01 h); maximum plasma concentration ( Cmax = 40.23 versus 36.31 μg/ml) and areas under the concentration-time curve (AUCs0– ∞ = 421.88 versus 274 μg h/ml. Based on comparisons of Cmax, Tmax, and AUCs0– ∞ between the actual data and single intraperitoneal (i.p.) data previously published, the s.c. administration exhibited slower disposition and higher absorbed amount. After multiple-dose administrations of 50 and 100 mg/kg every 12 h (07:00 and 19:00 h), steady-state plasma levels were lower than the computer prediction, and only slight accumulation was observed. In both dosing periods HEPP levels were similar in mothers and offspring at steady-state conditions. The high incidence of embryo death and reduced embryo weight at GD6–14 dosing compared to GD14–21 dosing suggest that embryos are more sensitive to the deleterious effects of HEPP than fetuses; however, the faster elimination observed at late gestation could also contribute to the lower toxicity observed during the fetal period. Because the maternal HEPP plasma levels and the AUC values were positively correlated with embryo/fetal toxicity end points, both pharmacokinetic parameters could be reliable indicators of offspring exposure and consequently of potential toxicity. These data suggest that the length of time that HEPP is present in the maternal plasma at a sufficiently high concentration could be determinant of adverse effects in the offspring.

Abstract P639: Sildenafil Treatment Improves Placental Levels of Placental Growth Factor in the Dahl Salt-Sensitive Pregnant Rat Model of Superimposed Preeclampsia

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana C Palei ◽  
Jennifer M Sasser ◽  
Joey P Granger
Keyword(s):  
Growth Factor ◽  
Umbilical Vein ◽  
Resistance Index ◽  
Placental Growth Factor ◽  
Trophoblast Invasion ◽  
Maternal Circulation ◽  
Pregnant Rats ◽  
Pregnant Rat

Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired trophoblast invasion followed by placental ischemia promotes the release of placental anti-angiogenic factors into the maternal circulation. These factors then elicit maternal endothelial dysfunction and hypertension by blocking the action of molecules such as the placental growth factor (PlGF). Inhibition of phosphodiesterase (PDE)-5 with sildenafil or other has been proposed as a potential therapy for PE; however, the mechanisms whereby PDE-5 inhibitors reduce blood pressure (BP) and improve uteroplacental perfusion during pregnancy are not clear. While previous studies have shown that PDE-5 inhibition induces PlGF production from human umbilical vein endothelial cells; it is unknown whether PDE-5 inhibitors also increase PlGF from placenta. Thus, the aim of this study was to evaluate whether sildenafil enhance placental secretion/production of PlGF in vitro and in vivo. In our in vitro protocol, we incubated placental villous explants from Sprague Dawley (SD) pregnant rats (n=4, 2-3 placentas per rat) at gestational day (GD)19 with different doses of sildenafil for 48h at 37°C under normoxia (8% O 2 ). PlGF-2 was measured in media of cultured explants by ELISA. We observed that sildenafil had no effect on PlGF-2 secretion from rat placental villi (vehicle: 562.7±46.6, 10nM: 559.3±39.5, 100nM: 556.4±35.9, 10uM: 546.2±37.5, and 100uM: 558.7±48.2pg/mg; P>0.05). In our in vivo protocol, we treated Dahl Salt-Sensitive (DS) pregnant rats (n=6-8 per group), which we had previously characterized as a model of superimposed PE, with sildenafil (50mg/kg per day, via food) from GD10 to 20. PlGF-2 was measured in placental homogenates by ELISA. While untreated DS dams exhibited an increase in BP and uterine artery resistance index (UARI) from baseline to late pregnancy, sildenafil-treated DS dams exhibited a significant decrease in BP and UARI. In addition, we found that placental levels of PlGF-2 were elevated in sildenafil-treated DS dams compared with untreated counterparts (1019±107.3 and 646.8±125.1pg/mg; P=0.0407). In conclusion, our findings suggest that the BP and UARI reduction in response to sildenafil may involve the indirect production of PlGF.

Role of pregnancy on insulin-induced vasorelaxation: the influence of angiotensin II receptors

2021 ◽  
Author(s):  
Betzabel Rodriguez-Reyes ◽  
Cecilia Tufiño ◽  
Ruth Mery López ◽  
Elvia Mera-Jimenez ◽  
Rosa Amalia Bobadilla Lugo
Keyword(s):  
Angiotensin Ii ◽  
Thoracic Aorta ◽  
Abdominal Aorta ◽  
Pregnant Rats ◽  
At1 Receptors ◽  
Pregnant Rat ◽  
Vasorelaxant Effect ◽  
Sensitizing Effect ◽  
At2 Receptors

Pregnancy is characterized by insulin resistance that is associated with increased angiotensin II (AngII) and insulin levels. Therefore, pregnancy may change insulin-induced vasodilation through changes in AngII receptors. Insulin-induced vasorelaxation was evaluated in phenylephrine-precontracted aortic rings of pregnant and non-pregnant rats, using a conventional isolated organ preparation. Experiments were performed in thoracic or abdominal aorta rings with or without endothelium in the presence and absence of L-NAME (10-5 M), losartan (10-7 M) or PD123319 (10-7 M). AT1 and AT2 receptors expression were detected by immunohistochemistry. Insulin-induced vasodilation was endothelium and NO dependent and decreased in the thoracic aorta but increased in the abdominal segment of pregnant rats. Insulin’s vasorelaxant effect was increased by losartan mainly on the thoracic aorta. PD123319 decreased insulin-induced vasorelaxation mainly in the pregnant rat abdominal aorta. AT1 receptors’ expression was decreased while AT2 receptors’ expression was increased by pregnancy. In conclusion, pregnancy changes insulin-induced vasorelaxation. Moreover, insulin vasodilation is tonically inhibited by AT1 receptors, while AT2 receptors appear to have an insulin-sensitizing effect. The role of pregnancy and AngII receptors differ depending on the aorta segment. These results shed light on the role of pregnancy and AngII receptors on the regulation of insulin-mediated vasodilation.

scholarly journals The effect of combined dietary iron, calcium and folk acid supplementation on apparent 65Zn absorption and zinc status in pregnant rats

1989 ◽  
Vol 62 (2) ◽  
pp. 415-423 ◽  
Author(s):  
Susan Southon ◽  
A. J. A. Wright ◽  
Susan J. Fairweather−Tait
Keyword(s):  
Folic Acid ◽  
Maternal Plasma ◽  
Folic Acid Supplementation ◽  
Zinc Status ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Acid Supplementation ◽  
Zn Concentration ◽  
Female Wistar Rats ◽  
Daily Intakes

In the present study the effect of combined iron, calcium and folic acid supplementation of the diet on 65Zn retention and zinc status was studied in the pregnant rat. Female Wistar rats were fed on a low-(8 μg/g) or high- (60 μg/g) Zn diet for 14 d and then mated overnight. After mating, half the rats were fed on the low- or high-Zn diet as before, whilst the other half were fed on similar diets supplemented with Fe, Ca and folic acid. The level of supplementation was chosen to reflect proportionately the possible increase in daily intakes of these nutrients by pregnant women. Rats which did not mate successfully were used as non-pregnant controls. On day 18 of pregnancy, each animal was given a meal of the appropriate diet labelled extrinsically with 65Zn, and on day 20 rats were killed. Carcass 65zn retention was lower in pregnant and non-pregnant rats fed on the supplemented diets compared with those fed on the unsupplemented diets. Rats which consumed the supplemented diets throughout pregnancy had reduced plasma Zn concentrations but femur and fetal Zn concentrations were unaffected. Maternal femur Ca and fetal Fe concentrations were lower in the high-Zn groups compared with rats fed on low-Zn diets. It was concluded that the risk of inducing fetal Zn depletion as a consequence of Fe, Ca and folic acid supplementation during pregnancy appeared to be slight. However, significant differences in 65Zn retention and maternal plasma Zn concentration in the supplemented groups, and reduced maternal bone Ca deposition and fetal Fe accretion in the high-Zn groups, indicated that it would seem wise to adopt a cautious approach to routine supplementation with individual minerals during pregnancy.

Effects of methyl-deficient diets on methionine and homocysteine metabolism in the pregnant rat

2012 ◽  
Vol 302 (12) ◽  
pp. E1531-E1540 ◽  
Author(s):  
Fiona A. Wilson ◽  
Grietje Holtrop ◽  
A. Graham Calder ◽  
Susan E. Anderson ◽  
Gerald E. Lobley ◽  
...  
Keyword(s):  
Folic Acid ◽  
Maternal Plasma ◽  
Limited Information ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Fetal Tissues ◽  
Maternal Liver ◽  
Flow Through ◽  
Total Homocysteine ◽  
Limited Diet

Although the importance of methyl metabolism in fetal development is well recognized, there is limited information on the dynamics of methionine flow through maternal and fetal tissues and on how this is related to circulating total homocysteine concentrations. Rates of homocysteine remethylation in maternal and fetal tissues on days 11, 19, and 21 of gestation were measured in pregnant rats fed diets with limiting or surplus amounts of folic acid and choline at two levels of methionine and then infused with l-[1-13C,2H3-methyl]methionine. The rate of homocysteine remethylation was highest in maternal liver and declined as gestation progressed. Diets deficient in folic acid and choline reduced the production of methionine from homocysteine in maternal liver only in the animals fed a methionine-limited diet. Throughout gestation, the pancreas exported homocysteine for methylation within other tissues. Little or no methionine cycle activity was detected in the placenta at days 19 and 21 of gestation, but, during this period, fetal tissues, especially the liver, synthesized methionine from homocysteine. Greater enrichment of homocysteine in maternal plasma than placenta, even in animals fed the most-deficient diets, shows that the placenta did not contribute homocysteine to maternal plasma. Methionine synthesis from homocysteine in fetal tissues was maintained or increased when the dams were fed folate- and choline-deficient methionine-restricted diets. This study shows that methyl-deficient diets decrease the remethylation of homocysteine within maternal tissues but that these rates are protected to some extent within fetal tissues.

Fetal growth inhibition and decreased thyroid activity after injection of oestradiol benzoate into pregnant rats

1982 ◽  
Vol 93 (1) ◽  
pp. 55-63 ◽  
Author(s):  
E. R. Kühn ◽  
M. Bollen ◽  
V. Darras
Keyword(s):  
Fetal Growth ◽  
Plasma Levels ◽  
Close Correlation ◽  
Maternal Plasma ◽  
Pregnant Rats ◽  
Fetal Plasma ◽  
Glucose Levels ◽  
Oestradiol Benzoate ◽  
Placental Blood ◽  
Circulating Levels

Pregnant rats were subcutaneously injected daily with 10 μg oestradiol benzoate (OB) and/or 1 mg bromocriptine starting on day 15 of gestation. After treatment with OB, but not bromocriptine, lower fetal body weight, fetal length and placental weight were observed. The administration of bromocriptine did not influence maternal plasma levels of prolactin, but fetal levels were decreased on day 22 of gestation. Oestradiol benzoate raised prolactin concentrations in maternal plasma on days 20 and 22, whereas fetal plasma levels were raised on day 22. This increase was counteracted by simultaneous administration of bromocriptine and OB, whereas impairment of fetal growth remained after treatment. A slight decline in fetal plasma levels of insulin was observed once, but thyroid content of triiodothyronine and thyroxine (T4) was decreased to a quarter and a third respectively of control levels in male and female fetuses of OB-treated rats, fetal circulating levels of T4 were also depressed. Maternal and fetal plasma glucose levels were decreased. A close correlation between T4 and placental or fetal weight was always present on day 22 of gestation. It was concluded that OB injected into pregnant rats will reach the fetal circulation as judged by increases in fetal plasma levels of prolactin. The observed fetal growth retardation after the OB injection was associated with thyroid deficiency, whereas plasma levels of prolactin and insulin were either not at all or only slightly altered. A direct effect of OB on placental blood flow and hence on the fetal food supply cannot, however, be excluded.

Endothelium and aortic contraction to endothelin-1 in the pregnant rat

2000 ◽  
Vol 78 (5) ◽  
pp. 372-377 ◽  
Author(s):  
Amadou Moctar Dièye ◽  
Alexis Gairard
Keyword(s):  
Receptor Antagonist ◽  
Late Pregnancy ◽  
Female Rats ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Endothelin 1 ◽  
Key Words Endothelin ◽  
Vasoconstrictor Peptide ◽  
Aortic Contraction

Endothelium-derived factors modulate tone and may be involved in hyporeactivity to vasoconstrictors, such as norepinephrine or angiotensin II, as has been previously described during gestation. The endothelium produces endothelin-1, a major vasoconstrictor peptide, therefore aortic contractions to endothelin-1 (10-10 to 3 ×10-7 M) were used to assess the role of the endothelium in pregnant Wistar rats (at 20 days of gestation). Late pregnancy is characterized by a significantly diminished systolic blood pressure in conscious rats (-17 mmHg, P < 0.001, n = 14). In pregnant and in age-matched nonpregnant female rats, endothelin-1 induced aortic contraction was greater when endothelium was present (at least P < 0.01). Indomethacin significantly reduced this contraction in aortic rings with intact endothelium in all groups. In aortic rings that had endothelium physically removed, contraction to endothelin-1 was greater in pregnant rats than in nonpregnant ones. Indomethacin decreased contraction of aortic rings in pregnant rats only. These results suggest an enhanced synthesis of vasoconstrictors by cyclooxygenases in vascular smooth muscle during pregnancy. In vessels with intact endothelium, we did not find hyporeactivity to endothelin-1 during late pregnancy. Contraction to endothelin-1 involved ETA receptors because it was decreased by BQ-123, an ETA receptor antagonist, whereas there was no significant change when using BQ-788, an ETB receptor antagonist. Key words: endothelin-1, endothelium, contraction, aorta, gestation.

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