Plasma uric acid levels do not correlate to plasma-evoked changes in endothelial function in women with preeclampsia.
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Arteries↗
Biomedical subjects
Philip N Baker
Publications and source records attributed to Philip N Baker.
Acute hyperglycemia in uterine arteries from pregnant, but not non-pregnant mice, enhances endothelium-dependent relaxation.
Poorly controlled diabetes in pregnancy, characterized by hypo- and hyperglycemia, is associated with adverse outcomes. We hypothesized that aberrant glucose levels affect vascular function in pregnancy. The effects of glucose concentration on constriction and endothelium-dependent relaxation in uterine arteries of normal C57BL/6 mice were examined. Ex-vivo arteries from 18 pregnant and 14 non-pregnant mice were mounted on a wire myograph, constricted with phenylephrine and relaxed with incremental doses of acetylcholine, in physiological saline solution containing 5 mmol/L glucose. Arteries were then exposed to solutions with 2, 5, 8 or 12 mmol/L glucose for 30 min and constriction/relaxation repeated. On altering glucose concentrations to 2, 8 or 12 mmol/L, maximal constriction was increased in arteries from pregnant but not from non-pregnant mice (paired t-test, p<0.05). Endothelium-dependent relaxation was enhanced at 12 mmol/L glucose in arteries from pregnant (two-way ANOVA, p<0.01), but not from non-pregnant mice. Endothelium-dependent relaxation in the uterine artery was pre-dominantly mediated by a non-nitric oxide/non-prostanoid mechanism, with a smaller contribution from nitric oxide, and no prostanoid-mediated relaxation. In summary, acute changes in glucose concentration alter both constriction and endothelium-dependent relaxation in uterine arteries of normal pregnant mice; these effects are unique to pregnancy.
Acetylcholine↗
Reactivity of human placental chorionic plate vessels from pregnancies complicated by intrauterine growth restriction (IUGR).
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.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Expression and function of potassium channels in the human placental vasculature.
In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.1, KV9.3, large-conductance Ca2+-activated K channel (BKCa), inward-rectified K+ channel (KIR)6.1, and two-pore domain inwardly rectifying potassium channel-related acid-sensitive K channels (TASK)1 in chorionic plate arteries, veins, and placental homogenate was assessed by RT-PCR and Western blot analysis. Functional activity of K channels was assessed pharmacologically in small chorionic plate arteries and veins by wire myography using 4-aminopyridine, iberiotoxin, pinacidil, and anandamide. Experiments were performed at 20, 7, and 2% oxygen to assess the effect of oxygenation on the efficacy of K channel modulators. KV2.1, KV9.3, BKCa, KIR6.1, and TASK1 channels were all demonstrated to be expressed at the message level. KV2.1, BKCa, KIR6.1, and TASK1 were all demonstrated at the protein level. Pharmacological manipulation of voltage-gated and ATP-sensitive channels produced the most marked modifications in vascular tone, in both arteries and veins. We conclude that K channels play an important role in controlling placental vascular function.
4-Aminopyridine↗
The effect of superoxide free radicals on human myometrial contractility in vitro.
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Adult↗
Phosphodiesterase-5 inhibitors and omental and placental small artery function in normal pregnancy and pre-eclampsia.
OBJECTIVES: In pre-eclampsia (PE), endothelium-dependent function of myometrial small arteries is markedly attenuated. The residual PE response is wholly NO mediated. We have previously demonstrated that PDE5 inhibition can improve endothelial function in myometrial small arteries from women with PE. We aimed to assess whether the effect of PDE5 inhibition in PE was myometrial artery specific. STUDY DESIGN: Small arteries were dissected from omental biopsies obtained at Caesarean section from normal pregnant women (NP, N = 20) and women with PE (N = 11). Chorionic plate small arteries were dissected from NP (N = 13) and PE (N = 11) placentae. Vasoconstriction (arginine vasopressin or thromboxane-mimetic U46619) and endothelial-dependent relaxation were assessed by wire and pressure myography. Constriction/relaxation curves were repeated post 1h incubation with PDE5 inhibitors UK-343664 or sildenafil citrate (0, 10 or 100 nM). RESULTS: Omental artery constriction was increased in PE. Omental vessel constriction was unaffected by PDE5 inhibition. Sildenafil citrate improved bradykinin-induced but not acetylcholine-induced relaxation of omental small arteries from NP women. PDE5 inhibition did not alter relaxation of omental arteries from women with PE. Placental small arteries were unaffected by PDE5 inhibition. CONCLUSION: Use of PDE5 inhibitors does not significantly alter endothelial-dependent relaxation in omental or placental small arteries from PE women.
Analysis of Variance↗
TASK channel expression in human placenta and cytotrophoblast cells.
OBJECTIVE: The multinucleate syncytiotrophoblast is the transporting epithelium of the human placental villus, formed throughout pregnancy by fusion and differentiation of underlying mononucleate cytotrophoblast cells. Similar to other epithelia, K+ channels will impact on syncytiotrophoblast transport properties during its development and differentiation. Therefore we investigated expression and activity of the two-pore domain K+ channels TASK1 and 2 in relation to gestation and differentiation, using villous tissue from first and third trimester and cultured cytotrophoblast cells at mononucleate and multinucleate stages of culture. METHODS: Quantitative real-time polymerase chain reaction (PCR), immunofluorescence, and 86Rb+ (K) efflux were used to investigate TASK channel expression and function. RESULTS: TASK2 mRNA expression was higher in first trimester than term (10 to 13 vs 38 to 40 weeks, P < .05). Other K+ alpha-subunit mRNAs, including TASK1, remained unaltered but the regulatory BKCa beta-subunit, like TASK2, was higher in first trimester than term (P < .001). Immunofluorescence showed that TASK2 had an intracellular localization within the trophoblast of first trimester villi but was less abundant and restricted to stem villi at term. TASK2 also showed intracellular localization in mononucleate cytotrophoblast cells in culture and expression was lost with multinucleation. By contrast, TASK1 was localised, independently of cell nucleation, to cytotrophoblast cell plasma membranes. 86Rb+ (K) efflux was measured from multinucleated cytotrophoblast cells. Both basal and pH 8.0-stimulated efflux was inhibited by the TASK1 antagonist anandamide (n = 5 for both conditions; P < .01 and P < .001, respectively). CONCLUSION: TASK1 and 2 are expressed in placental trophoblast cells and TASK1 activity may have a role in regulating syncytiotrophoblast homeostasis and/or solute transport functions.
Arachidonic Acids↗
Invasive trophoblasts stimulate vascular smooth muscle cell apoptosis by a fas ligand-dependent mechanism.
During pregnancy, trophoblasts migrate from the placenta into uterine spiral arteries, transforming them into wide channels that lack vasoconstrictive properties. In pathological pregnancies, this process is incomplete. To define the fundamental events involved in spiral artery remodeling, we have studied the effect of trophoblasts on vascular smooth muscle cells (SMCs). Here we demonstrate for the first time that apoptosis of SMCs can be initiated by invading trophoblasts. When trophoblasts isolated from normal placenta (primary trophoblasts) or conditioned medium was perfused into spiral or umbilical artery segments, apoptosis of SMCs resulted. Culture of human aortic SMCs (HASMCs) with primary trophoblasts, primary trophoblast-conditioned medium, or a trophoblast-derived cell line (SGHPL-4) also significantly increased SMC apoptosis. Fas is expressed by spiral artery SMCs, and a Fas-activating antibody triggered HASMC apoptosis. Furthermore, a Fas ligand (FasL)-blocking antibody significantly inhibited HASMC apoptosis induced by primary trophoblasts, SGHPL-4, or trophoblast-conditioned medium. Depleting primary trophoblast-conditioned medium of FasL also abrogated SMC apoptosis in vessels in situ. These results suggest that apoptosis triggered by the release of soluble FasL from invading trophoblasts contributes to the loss of smooth muscle from the walls of spiral arteries during pregnancy.
Apoptosis↗
Delivering twins--perceptions and expectations.
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Cesarean Section↗
Sphingosine-1-phosphate acts via rho-associated kinase and nitric oxide to regulate human placental vascular tone.
Sphingosine-1-phosphate (S1P), a bioactive lipid released from activated platelets, has been demonstrated in animal models to regulate vascular tone through receptor-mediated activation of Rho-associated kinase 1 and nitric oxide synthase 3. The role of S1P in regulation of human vascular tone (particularly during pregnancy, with its unique vascular adaptations and localized platelet activation) is unknown. We hypothesized that S1P would constrict small placental arteries through activation of Rho-associated kinases with modulation by nitric oxide. Reverse transcription-polymerase chain reaction of chorionic plate artery preparations detected mRNAs encoding all five receptors for S1P, and S1P induced dose-dependent vasoconstriction of both chorionic plate and stem villous isobarically mounted arteries, which at 10 micromol/L was 32.9% +/- 3.86% (mean +/- SEM) and 34.6% +/- 7.01%, respectively. In stem villous arteries, S1P-induced vasoconstriction was enhanced significantly following inhibition of nitric oxide synthases with N(G)-nitro-L-arginine methyl ester (100 micromol/L, 52.6% +/- 6.28%, P < 0.05). The S1P-induced vasoconstriction was reversed by Y27632, an inhibitor of Rho-associated kinases (10 micromol/L) in both chorionic plate (to 14.9% +/- 4.95%) and stem villous arteries (to 2.71% +/- 6.13%). The S1P added to alpha-toxin-permeabilized, isometrically mounted chorionic plate arteries bathed in submaximal Ca(2+)-activating solution induced Ca(2+)-sensitization of constriction, which was 47.7% +/- 10.0% of that occurring to maximal Ca(2+)-activating solution. This was reduced by Y27632 to 18.4% +/- 18.4%. Interestingly, S1P-induced vasoconstriction occurred in all isobarically mounted arteries but was inconsistent in isometrically mounted chorionic plate arteries. In summary, S1P-induced vasoconstriction in human placental arteries is mediated by increased Ca(2+)-sensitization through activation of Rho-associated kinases, and this vasoconstriction also is modulated by nitric oxide. Identification of these actions of S1P in the placental vasculature is important for understanding both normal and potentially abnormal vascular adaptations with pregnancy.
Arteries↗
Outcomes of labours augmented with oxytocin.
OBJECTIVE: To highlight the differences in mode of delivery between women augmented with intravenous oxytocin because of failure to progress in labour with those who labour without the need for augmentation. STUDY DESIGN: An incidence study over a 5-year-period in a tertiary referral hospital comparing 1097 nulliparous women who were augmented in labour with 2745 nulliparous women who did not need augmentation. Only labours of spontaneous onset in the pregnancies of women at term were studied. The incidence of pregnancy outcomes were assessed by presenting estimates of relative risk (RR) and their 95% confidence intervals (CI). RESULTS: Only 51.1% of women who received augmentation achieved a normal vaginal delivery compared with 76.5% of women who did not need augmentation (RR 0.67; CI 0.63-0.71). Contributory factors to this disparity included a greater number of Caesarean sections (14.4% versus 6.6%; RR 2.18 CI 1.74-2.67), forcep deliveries (12.8% versus 5.3%; RR 2.41 CI 1.93-3.01) and ventouse deliveries (21.7% versus 11.5%; RR 1.89 CI 1.62-2.21) being performed among augmented labours as compared to normal progressive labours. CONCLUSION: Significant improvements in the management of labours which fail to progress are needed if normal vaginal delivery rates are to approach those seen in labours which progress without the need for augmentation.
Adult↗
Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
The effect of vascular origin, oxygen, and tumour necrosis factor alpha on trophoblast invasion of maternal arteries in vitro.
Extravillous trophoblasts (EVTs) invade and remodel uterine spiral arteries. Regulatory factors may include inherent vessel susceptibility, local oxygen levels and tumour necrosis factor alpha (TNFalpha). We have used an in vitro model to investigate interstitial and endovascular invasion of myometrial spiral arteries from pregnant and non-pregnant uteri and also omental arteries. To model endovascular invasion, fluorescent-labelled EVTs were perfused into the lumen of these dissected vessels. For interstitial invasion, labelled EVTs were layered on top. Cultures were either maintained in 17% or 3% oxygen, or cultured with TNFalpha. The invasion of arteries from pregnant women occurred via both routes at 17% oxygen, with endovascular invasion more efficient than interstitial. In omental arteries and spiral arteries from non-pregnant women, endovascular invasion was limited. Endovascular and interstitial invasion were lower in all arteries at 3% oxygen. Typically, endovascular events were clustered, with an associated disruption in the adjacent endothelium and smooth muscle. A role for TNFalpha in limiting invasion was also supported. In conclusion, priming of uterine arteries may be necessary prior to EVT invasion. Oxygen is a sensitive regulator within this physiological model and increased invasion at higher pO2 may explain the homing of EVT to maternal arteries rather than veins. Adequate vascular transformation may therefore rely on a balance between vascular receptivity, oxygen partial pressure, and exposure to inflammatory mediators.
Arteries↗
Remodeling of myometrial radial arteries in preeclampsia.
OBJECTIVE: This study was undertaken to test for structural differences between myometrial radial arteries isolated from women having normal pregnancies and pregnancies complicated by preeclampsia and intrauterine growth restriction. STUDY DESIGN: Pressure myography was used to study myometrial radial arteries obtained at cesarean section. With the use of a transilluminating system, lumen diameter, wall thickness, wall/lumen ratio, distensibility and stress-strain relationship were studied through a range of pressures. Arteries were then fixed in glutaraldehyde, embedded in resin, cross-sectioned, and studied in greater detail by light and electron microscopy. RESULTS: Pressure myography showed that arteries from women with preeclampsia had a reduced lumen diameter, thicker wall, and greater wall/lumen ratio compared with vessels isolated from women with normal pregnancy. Light microscopy indicated an identical media content remodeled around a smaller lumen. Electron microscopy indicated enlarged extracellular spaces in the media but no change in myocyte profile size or number. There was no clear evidence of structural changes in myometrial radial arteries isolated from women with intrauterine growth restriction compared with normal pregnancy. No differences in vessel distensibility or stress-strain relationships were detected in complicated pregnancies. CONCLUSION: The changes observed in myometrial radial arteries isolated from women with preeclampsia are due to inward eutrophic remodeling. Alterations in these vessels may contribute to increased uterine vascular resistance in preeclampsia.
Adult↗
The involvement of Rho-associated kinases in agonist-dependent contractions of human maternal and placental arteries at term gestation.
OBJECTIVE: The purpose of this study was to assess the involvement of rho kinase (ROK) in agonist-dependent contraction of omental, myometrial, and placental arteries of pregnant women at term. STUDY DESIGN: Wire myography was used to assess if contractions of intact or alpha-toxin-permeabilized arteries obtained from women at elective cesarean section were influenced by the ROK inhibitor Y-27632. RESULTS: Western blotting indicated the presence of ROKalpha in each of the 3 tissue types. In intact human omental, myometrial, or placental arteries, Y-27632 dose-dependently reduced constrictions to the thromboxane-mimetic U46619. In permeabilized vessels, U46619 induced substantial Ca(2+)-sensitization of contraction that was inhibited by Y27632. The phosphatase inhibitor calyculin A induced a Ca(2+)sensitization of contraction similar to that of U46619 in permeabilized omental arteries that was unaffected by Y-27632, suggesting that ROK may signal via myosin phosphatase in these vessels. CONCLUSION: These results are the first report of the involvement of ROK in the receptor-coupled constriction of intact and permeabilized arteries from pregnant women.
Amides↗
Localization of TASK and TREK, two-pore domain K+ channels, in human cytotrophoblast cells.
OBJECTIVE: Two-pore domain K+ channels (K2P), an emerging K+ channel subfamily, contribute to setting membrane potential in both electrically excitable and nonexcitable cells and, as such, influence cellular function. The multinucleate syncytiotrophoblast of human placenta, formed from the fusion of mononucleate cytotrophoblast cells, is a transporting epithelium whose function likely depends on the activity of K+ channels. We have therefore investigated the gene expression of two members of this family, TASK and TREK, in cultured human cytotrophoblast cells, and have also investigated protein expression in cytotrophoblast cells and placenta. METHODS: We used reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunocytochemistry to investigate the gene and protein expression of TASK and TREK isoforms in both isolated cytotrophoblast cells and term placental tissue. RESULTS: In cytotrophoblast cells, mRNAs encoding TASK1, 2, 4, 5, and TREK1 were detected, whereas weak or no signals were observed for TASK3 and TREK2. Western blotting for TASK1 in cytotrophoblast cells gave two bands of approximately 78 and 150 kd; TREK1 gave bands of approximately 90 and 130 kd. TASK1 immunofluorescence in placenta colocalized with cytokeratin-7, a trophoblast-specific marker. TREK1 predominantly stained cells around the villous perimeter and this staining was colocalized with propidium iodide nuclear staining. CONCLUSION: Human cytotrophoblast cells from term placenta are a site of expression for various K2P genes, two of which, namely, TASK1 and TREK1, are transcribed into protein.
Blotting, Western↗
Effects of oxygen tension and normalization pressure on endothelin-induced constriction of human placental chorionic plate arteries.
OBJECTIVES: Fetoplacental blood vessels constrict in response to endothelin (ET-1) or reduced oxygen tension in the placental cotyledon perfused in vitro. In nonplacental resistance arteries, hypoxia and ET-1 induce constriction by promoting Ca2+ influx into smooth muscle through membrane ion channels, which include voltage-gated Ca2+ channels (VGCCs). We hypothesized that VGCCs are involved in ET-1-induced constriction of fetoplacental resistance vessels and that their contribution to constriction is enhanced at low oxygen tension. METHODS: Chorionic plate small arteries from term placentas were studied using parallel wire myography. Arteries were normalized at 0.9 of L(5.1 kPa) ("low stretch" approximately 25 mm Hg; approximating physiologic vascular pressure) or 0.9 of L(13.3 kPa) ("high stretch" approximately 42 mm Hg) and experiments performed at oxygen tensions of 156, 38, and 15 mm Hg. RESULTS: When chorionic plate arteries were normalized at low stretch, oxygen tension did not affect constriction to ET-1. Nifedipine (10(-4) M), a blocker of L-type VGCCs, inhibited ET-1 (EC80)-induced constriction to a similar extent at each oxygen tension (52% to 64% inhibition). In contrast, when arteries were normalized at high stretch, constriction to ET-1 was greater at 38 than at 156 or 15 mm Hg oxygen and nifedipine inhibition of ET-1-induced constriction was greater at 38 and 15 mm Hg than at 156 mm Hg oxygen. CONCLUSIONS: VGCCs and nifedipine-insensitive processes underlie the contractile response of chorionic plate arteries to ET-1 and their relative contribution to vasoconstriction is modulated by oxygen tension when vessels are normalized at high stretch. However, contrary to our hypothesis, the response of chorionic plate arteries to ET-1 is not modulated by oxygen when vessels are normalized at physiologic pressure.
Arteries↗
Excessive stimulation of poly(ADP-ribosyl)ation contributes to endothelial dysfunction in pre-eclampsia.
1. Pre-eclampsia is a serious pregnancy disorder associated with widespread activation of the maternal vascular endothelium. Recent evidence implicates a role for oxidative stress in the aetiology of this condition. 2. Reactive oxygen species, particularly superoxide anions, invokes endothelial cell activation through many pathways. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes). 3. We have studied whether the loss of endothelial function in pre-eclampsia is dependent on PARP activity. Endothelium-dependent responses of myometrial arteries were tested following exposure to either plasma from women with pre-eclampsia or normal pregnant women in the presence and absence of a novel potent inhibitor of PARP, PJ34. Additional effects of plasma and PJ34 inhibition were identified in microvascular endothelial cell cultures. 4. In myometrial arteries, PARP inhibition blocked the attenuation of endothelium-dependent responses following exposure to plasma from women with pre-eclampsia. In endothelial cell cultures, plasma from pre-eclamptics induced measurable oxidative stress and a concomitant increase in PARP activity and reduction in cellular ATP. Again, these biochemical changes were reversed by PJ34. 5. These results suggest that PARP activity plays a pathogenic role in the development of endothelial dysfunction in pre-eclampsia and promotes PARP inhibition as a potential therapy in this condition.
Adenosine Triphosphate↗