15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Fetal-Growth-Retardation

Intrauterine growth restriction (IUGR) is one of the most common pathologies of pregnancy. The cardiovascular consequences of IUGR do not disappear in adulthood and can manifest themselves in pathological alterations of vasomotor control. The hypothesis was tested that IUGR weakens anticontractile influence of NO and augments procontractile influence of Rho-kinase in arteries of adult offspring. To model IUGR in the rat, dams were 50% food restricted starting from the gestational day 11 till delivery. Mesenteric and coronary arteries of male offspring were studied at the age of 3 months using wire myography, qPCR, and Western blotting. Contractile responses of mesenteric arteries to α

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amides; Animals; Coronary Vessels; Disease Models, Animal; Female; Fetal Growth Retardation; Male; Mesenteric Arteries; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase Type III; Pregnancy; Pyridines; Rats, Wistar; rho-Associated Kinases

Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic human HDP in the last trimester, we calculated placental efficiencies based on fetal and placental weights; quantified spongiotrophoblast and labyrinth thicknesses and vascular density within these layers; examined whether hypoxia signaling pathway involving vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1, VEGFR2) and matrix metalloproteinases (MMPs) contributed to vascular change; and examined nutrient transporter abundance including glucose transporters 1 and 3 (GLUT1, GLUT3), neutral amino acid transporters 1, 2, and 4 (SNAT1, SNAT2, and SNAT4), fatty acid transporters 2 and 4 (FATP2, FATP4), and fatty acid translocase (CD36) from embryonic day 15.5 to 19 in a 20-day C57Bl/6J mouse gestation. We conclude that early-to-mid gestation hypertensive placentae show compensatory mechanisms to preserve fetal growth by increasing placental efficiencies and maintaining abundance of important nutrient transporters. As placental vascular network diminishes over late hypertension, placental efficiency diminishes and fetal growth fails. Neither hypoxia signaling pathway nor MMPs mediated the vascular diminution in this model. Hypertensive placentae surprisingly exhibit a sex-differential expression of nutrient transporters in late gestation despite showing fetal growth failure in both sexes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amino Acid Transport Systems, Neutral; Animals; Disease Models, Animal; Fatty Acid Transport Proteins; Female; Fetal Growth Retardation; Glucose Transport Proteins, Facilitative; Matrix Metalloproteinases; Mice; Placenta; Placentation; Pregnancy; Signal Transduction; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), and adrenomedullin2 (ADM2)/intermedin are potent vasorelaxant peptides considered to play a role in the adaptive mechanisms in rat pregnancy through increased vasodilation in mesenteric and uterine artery.. This study was designed to demonstrate the response of omental arteries (OA) to vasoactive peptides CGRP, ADM, and ADM2 in pregnancy complications such as fetal growth restriction (FGR), and assess the changes in the expression of their receptor components in segments of OA from FGR pregnancy compared to the control.. The findings for this study are: 1) relaxation responses of OA were higher for bradykinin (78.55 ± 3.91 vs 52.67 ± 2.19; P < .05) in pregnancy with FGR compared to the normal, 2) relaxation response of OA segments to CGRP was similar with no change in the expression of G-protein couple receptor-calcitonin receptor-like receptor complex in normal healthy pregnancy and pregnancy complicated by FGR, 3) maximal relaxation response of OA were significantly (P < .05) lower for both ADM (18.2 ± 6.7 vs 38 ± 2.5) and ADM2 (26.9 ± 6.7 vs 48 ± 2.6) along with decreases in their respective ligand-receptor complex in FGR compared to the normal pregnancies, 4) expression of calcitonin receptor-like receptor mRNA was higher but its immunoreactivity was lower in OA from FGR pregnancy compared to the normal, and 5) mRNA and protein levels of RAMP1, RAMP2, and RAMP3 were lower in OA isolated from FGR pregnancies compared to the normal.. The current study demonstrates that FGR is associated with an increase in the sensitivity of OA to bradykinin and decreased sensitivity for ADM and ADM2 ligand-receptor system with no change in the response for CGRP compared to the normal healthy pregnancy, and suggests a potential role for ADM and ADM2 in the pathophysiology of maternal vasculature in FGR pregnancy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenomedullin; Arteries; Bradykinin; Calcitonin Gene-Related Peptide; Case-Control Studies; Female; Fetal Growth Retardation; Gene Expression Regulation; Humans; In Vitro Techniques; Omentum; Peptide Fragments; Peptide Hormones; Pregnancy; Vasodilation

Fetal growth restriction (FGR) is a serious pregnancy complication, resulting in significant perinatal morbidity and mortality. Increased vascular resistance in the fetoplacental circulation is a hallmark of FGR and is associated with enhanced vasoconstriction of the resistance arteries in the placenta, the chorionic plate arteries (CPAs). Although the cause is unknown, FGR is associated with excess exposure to glucocorticoids (GCs), key mediators of vascular resistance in the systemic circulation. We hypothesized that GCs alter CPA reactivity, thereby contributing to the altered blood flow dynamics seen in FGR. We aimed to examine the acute and chronic effects of GCs on CPA reactivity and the operational mechanisms. Glucocorticoid receptors were highly expressed by CPA. 11β-Hydroxysteroid isoenzyme type 2 was detected within the endothelium, whereas 11β-hydroxysteroid isoenzyme type 1 was absent. Acute GC treatment significantly attenuated U46619-induced constriction. This effect was reversed by cotreatment with mifepristone or an endothelial NOS inhibitor. In contrast, chronic GC treatment potentiated U46619 constriction in a dose-dependent manner, which was partially abolished by mifepristone cotreatment. Similar effects were observed using a novel nonsteroidal glucocorticoid receptor-specific agonist. Chronic treatment with GCs altered the expression of several vasoactive factors, including thromboxane and bradykinin receptors, prokineticin-1, cyclooxygenase-2, and endothelial NOS. In summary, acute and chronic GC treatment exerts contrasting effects on CPA vasoreactivity. These opposing effects are consistent with temporal actions in other vascular beds and reflect activation of distinct nongenomic and genomic pathways. Chronic exposure to elevated GCs may contribute to the raised vascular resistance observed in the fetoplacental circulation in FGR.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arteries; Carbenoxolone; Chorion; Dexamethasone; Female; Fetal Growth Retardation; Glucocorticoids; Humans; Hydrocortisone; Mifepristone; Placenta; Placental Circulation; Pregnancy; Vasoconstriction; Vasodilation

Agonist-induced tone oscillations (rhythmic contractions and relaxations) occur in vascular beds to allow acute regulation of volume flow and thus the delivery of oxygen and nutrients to the tissue. Mechanisms responsible for the control of human placental vasomotor tone and blood flow are poorly characterized. This study aimed to characterise thromboxane-induced tone oscillations in human placental and myometrial arteries. Chorionic plate and myometrial arteries obtained from biopsies at term were mounted for isometric tension measurement. Tone oscillations were observed in chorionic arteries only when exposed to sub-maximal (<1 microM) concentrations of U46619. Slow (mean+/-SEM) frequency (2.6+/-0.5 per hour), large amplitude (39+/-7% of peak contraction) tone oscillations were elicited by 0.03 microM U46619 (n=18). In the presence of the nitric oxide synthase (NOS) inhibitor l-NNA (100 microM) the amplitude was significantly reduced (40+/-13% to 18+/-8%, P<0.05, n=6), frequency was unaltered and the bradykinin-dependent vasodilator response was reduced (68+/-13% to 40+/-19%, P<0.05, n=6). Myometrial arteries exposed to 1 microM U46619 developed tone oscillations within 10 min, which increased in amplitude over 30min occurring at relatively constant frequency. The mean amplitude of oscillations at 30 min (31+/-7%, n=16) was similar to that in chorionic arteries but the occurrence more frequent (42.8+/-9.7 per hour, P<0.001). Inhibition of NOS did not alter tone oscillations in myometrial arteries. Tone oscillations in chorionic arteries from pre-eclamptic and growth restricted (FGR) pregnancies were reduced in amplitude whereas those in myometrial arteries had increased frequency. Inhibition of NOS further reduced oscillation amplitude in chorionic arteries from FGR pregnancies. The alterations may contribute to the vasculopathology of these conditions, or, may represent compensatory mechanisms to maintain a matching of materno-placental blood flow.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arteries; Birth Weight; Blood Pressure; Bradykinin; Chorion; Female; Fetal Growth Retardation; Humans; Muscle Tonus; Muscle, Smooth, Vascular; Myography; Myometrium; Nitric Oxide; Nitroarginine; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Vasoconstriction; Vasodilation

There is now extensive evidence suggesting that intrauterine perturbations are linked with an increased risk of developing cardiovascular disease. Human epidemiological studies, supported by animal models, have demonstrated an association between low birth weight, a marker of intrauterine growth restriction (IUGR), and adult cardiovascular disease. However, little is known of the early influence of IUGR on the fetal heart and vessels. The aim of this study was to determine the effects of late gestational IUGR on coronary artery function and cardiomyocyte maturation in the fetus. IUGR was induced by placental embolization in fetal sheep from 110 to 130 days of pregnancy (D110-130); term approximately D147; control fetuses received saline. At necropsy (D130), wire and pressure myography was used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in small branches of left descending coronary arteries. Myocardium was dissociated for histological analysis of cardiomyocytes. At D130, IUGR fetuses (2.7 +/- 0.1 kg) were 28% lighter than controls (3.7 +/- 0.3 kg; P = 0.02). Coronary arteries from IUGR fetuses had enhanced responsiveness to the vasoconstrictors, angiotensin II and the thromboxane analogue U46619, than controls (P < 0.01). Endothelium-dependent and -independent relaxations were not different between groups. Coronary arteries of IUGR fetuses were more compliant (P = 0.02) than those of controls. The incidence of cardiomyocyte binucleation was lower in the left ventricles of IUGR fetuses (P = 0.02), suggestive of retarded cardiomyocyte maturation. We conclude that late gestational IUGR alters the reactivity and mechanical wall properties of coronary arteries and cardiomyocyte maturation in fetal sheep, which could have lifelong implications for cardiovascular function.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Bradykinin; Cell Differentiation; Coronary Vessels; Endothelium, Vascular; Female; Fetal Growth Retardation; Heart; Muscle, Smooth, Vascular; Myocytes, Cardiac; Pregnancy; Sheep; Vasoconstrictor Agents; Vasodilator Agents

A successful pregnancy is dependent on liberal placental perfusion via the maternal and fetal circulations. Doppler waveform analyses of umbilical arteries suggest increased resistance to flow in the fetoplacental circulation of pregnancies complicated by intrauterine growth restriction (IUGR). Neither the site nor the mediators responsible for this altered vascular reactivity are known, to date. In placentas in normal pregnancy, reduced oxygenation promotes contraction of the in vitro-perfused placental cotyledon and modulates agonist-induced contraction of chorionic plate arteries and veins. Placental oxygenation has also been suggested to be reduced in IUGR. We tested the hypothesis that oxygen tension could directly modify placental chorionic plate vessel vasoreactivity in IUGR. Small arteries and veins from the chorionic plate were dissected from biopsies from placentas of pregnancies complicated by IUGR and were studied using parallel wire myography. Vasoconstriction at 20%, 7%, and 2% oxygen was assessed utilizing the thromboxane mimetic U46619. Experiments were also performed in the presence of 4-aminopyridine (4AP), a blocker of voltage-gated potassium channels. Increased oxygenation reduced venous vasoconstriction but did not modify arterial vasoconstriction. 4AP increased basal tone in arteries and veins. We suggest that venoconstriction in response to hypoxia may provide a mechanism for increased fetoplacental vascular resistance associated with IUGR.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 4-Aminopyridine; Adolescent; Adult; Arteries; Dose-Response Relationship, Drug; Female; Fetal Growth Retardation; Humans; In Vitro Techniques; Infant, Newborn; Myography; Oxygen; Placenta; Placental Circulation; Potassium Channel Blockers; Pregnancy; Vasoconstriction; Vasoconstrictor Agents; Veins

Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR and to assess whether sildenafil citrate could improve vasodilatation in FGR pregnancies.. Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) before and after incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate.. We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries.. We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Arginine Vasopressin; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Female; Fetal Growth Retardation; Humans; Myometrium; Phosphodiesterase Inhibitors; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasodilation

In fetal growth restriction (FGR) abnormal umbilical artery (UA) Doppler waveform indices suggest increased vascular resistance and impaired placental blood flow. This study aimed to determine whether UA Doppler waveform indices were related to the vasoreactivity of placental chorionic plate small arteries in normal and FGR pregnancies.. UA Doppler waveform analysis was performed 24 h before delivery in 23 normal term and 15 FGR pregnancies. Post-delivery responses of chorionic plate arteries to vasoactive agents were examined using the technique of wire myography.. Altered vascular reactivity to agonists was demonstrated in chorionic plate arteries in FGR pregnancy. Constriction to U46619 (thromboxane mimetic) and relaxation to sodium nitroprusside (nitric oxide donor) were significantly increased in the arteries of FGR pregnancies compared with normal pregnancies. No relationship existed between Doppler indices and chorionic plate responses in normal or FGR pregnancies.. Fetoplacental vascular reactivity is altered in FGR pregnancy independently of UA Doppler waveform indices. Altered function may be additive to the pathophysiology underlying abnormal Doppler waveforms and could contribute to the inappropriate control of vascular tone in FGR.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Case-Control Studies; Chorion; Female; Fetal Growth Retardation; Humans; In Vitro Techniques; Myography; Nitroprusside; Placenta; Pregnancy; Statistics, Nonparametric; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

(1) To investigate a possible association between myometrial and placental artery vasoreactivity and perfusion at the basal and chorionic plates, respectively. (2) To confirm that myometrial arteries from women with pre-eclampsia and intrauterine growth restriction exhibit an attenuated endothelium-dependent vasodilatory response.. Women with normal pregnancy, pre-eclampsia and intrauterine growth restriction had a magnetic resonance scan to assess placental perfusion using a technique called intravoxel incoherent motion. At delivery, myometrial and chorionic plate placental arteries were assessed on a wire myograph. Vessels were pre-constricted with the thromboxane mimetic U46619 and dilated with incremental doses of bradykinin.. Pre-constricted myometrial arteries from women with pre-eclampsia or intrauterine growth restriction exhibited an attenuated vasodilatory response to bradykinin, compared with normal pregnancy (P < 0.0001). Pre-constricted placental arteries exhibited a minimal vasodilatory response in all three groups of women (P = 0.10). Maximal constrictor and vasodilatory responses of myometrial arteries were not associated with the perfusing fraction at the basal plate. Maximal constrictor and vasodilatory responses of chorionic plate placental arteries were not associated with the perfusing fraction at the chorionic plate.. We confirm that myometrial arteries from women with pre-eclampsia or intrauterine growth restriction exhibit an attenuated endothelium-dependent vasodilatory response. Apart from vasoreactivity of small arteries, other factors may be involved in the control of placental perfusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Analysis of Variance; Arteries; Female; Fetal Growth Retardation; Humans; Myometrium; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents; Vasodilation

Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Vessels; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Male; Mice; Receptors, Thromboxane; Thromboxane A2

This study on the human umbilical artery was undertaken in order to elucidate possible correlations between changes in response to vasoactive substances in vitro and abnormal umbilical artery flow velocity waveforms in vivo associated with preeclampsia and intrauterine growth retardation. The vascular reactivity to endothelin-1, noradrenalin, serotonin, the thromboxane A2 analogue U46619, substance P and prostacyclin was determined in umbilical artery segments from 13 normal pregnancies and 29 pregnancies complicated with preeclampsia and/or intrauterine growth retardation with normal or abnormal umbilical flow velocity waveforms. The contractile effect in vitro of endothelin-1 and noradrenalin was reduced in segments from pregnancies complicated by abnormal umbilical flow velocity waveforms in vivo. No differences were detected in the contractile effect of serotonin and U46619, or in the relaxatory effect of substance P and prostacyclin. In conclusion, endothelin-1- and noradrenalin-related mechanisms could be involved in the abnormal umbilical flow velocity waveforms associated with preeclampsia and intrauterine growth retardation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Blood Flow Velocity; Dose-Response Relationship, Drug; Endothelins; Epoprostenol; Female; Fetal Growth Retardation; Hemodynamics; Humans; Muscle, Smooth, Vascular; Norepinephrine; Pre-Eclampsia; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Serotonin; Substance P; Thromboxane A2; Ultrasonography, Doppler; Umbilical Arteries; Vasoconstriction; Vasoconstrictor Agents