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Biomedical subjects

Philip N Baker

Publications and source records attributed to Philip N Baker.

At least 37 records · Page 2Linked to original sources
PubMed2005

MMP-2 levels are elevated in the plasma of women who subsequently develop preeclampsia.

OBJECTIVE: To determine levels of matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in the plasma of women destined to develop preeclampsia prior to the onset of clinical disease. STUDY DESIGN: Plasma samples were taken from women whose pregnancies were subsequently complicated by preeclampsia and from normal pregnant women at 22 and 26 weeks and at delivery or diagnosis. Following equal protein loading, MMP-2 and 9 and TIMP-1 and 2 were quantified using zymography and Western blot analysis, respectively. RESULTS: Plasma MMP-2 levels were significantly elevated at 22 weeks (p = 0.02) and at diagnosis (p = 0.003) in the preeclampsia group, but there was no difference at 26 weeks. TIMP-1 levels were significantly reduced in the preeclampsia group at 26 weeks (p = 0.0002), but TIMP-2 levels were not quantifiable. CONCLUSION: At all three gestational time points an imbalance in the MMP-2:TIMP-1 ratio was found in patients who subsequently developed preeclampsia. We speculate that increased net MMP-2 activity may contribute to the endothelial dysfunction that is central to the pathophysiology of preeclampsia.

Adult↗
PubMed2005

A comparison of fetal organ measurements by echo-planar magnetic resonance imaging and ultrasound.

OBJECTIVES: To compare fetal organ size measured using echo-planar magnetic resonance imaging and 2D ultrasound. To determine the relative accuracy with which each technique can predict fetal growth restriction. DESIGN: A cross sectional, observational study comparing two different measurement techniques against a gold standard, in a normal clinical population and an abnormal population. SETTING AND POPULATION: Seventy-four pregnant women (33 who were ultimately found to be normal and 37 with fetal growth restricted fetuses) were recruited from the City Hospital Nottingham UK to be scanned once (at various gestations). METHODS: Each fetus had a standard ultrasound biometry assessment followed by magnetic resonance imaging measurement of organ volumes. MAIN OUTCOME MEASURES: For each measurement for both techniques, the normal population was plotted with 90% confidence intervals. Fetal growth restricted subjects were compared with the normal population using this plot; 2 x 2 tables were created for each measurement. This was used to calculate the relative sensitivities and positive predictive value of the different measurements. A Bland-Altman plot was used to compare the ultrasound and magnetic resonance imaging measurements of fetal weight. RESULTS: Brain sparing was seen in ultrasonic head circumference measurements, but an overall reduction in fetal growth restriction brain volume was apparent using magnetic resonance imaging at late gestations. Across the whole range of gestational ages, ultrasound assessment of fetal weight was the best predictor of fetal growth restriction. CONCLUSION: Ultrasound fetal weight assessment appears to identify more fetuses with fetal growth restriction than abdominal circumference. The brain sparing apparent in ultrasonic head circumference measurements of fetuses with fetal growth restriction masks a reduction in brain volume observed with magnetic resonance imaging.

Abdomen↗
PubMed2005

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium.

Two-pore domain K+ channels are an emerging family of K+ channels that may contribute to setting membrane potential in both electrically excitable and non-excitable cells and, as such, influence cellular function. The human uteroplacental unit contains both excitable (e.g. myometrial) and non-excitable cells, whose function depends upon the activity of K+ channels. We have therefore investigated the expression of two members of this family, TWIK (two-pore domain weak inward rectifying K+ channel)-related acid-sensitive K+ channel (TASK) and TWIK-related K+ channel (TREK) in human myometrium. Using RT-PCR the mRNA expression of TASK and TREK isoforms was examined in myometrial tissue from pregnant women. mRNAs encoding TASK1, 4 and 5 and TREK1 were detected whereas weak or no signals were observed for TASK2, TASK3 and TREK2. Western blotting for TASK1 gave two bands of approximately 44 and 65 kDa, whereas TREK1 gave bands of approximately 59 and 90 kDa in myometrium from pregnant women. TASK1 and TREK1 immunofluorescence was prominent in intracellular and plasmalemmal locations within myometrial cells. Therefore, we conclude that the human myometrium is a site of expression for the two-pore domain K+ channel proteins TASK1 and TREK1.

Blotting, Western↗
PubMed2004

Increased myogenic responses in uterine but not mesenteric arteries from pregnant offspring of diet-restricted rat dams.

Results of epidemiological and animal studies suggest a link between poor in utero growth and cardiovascular disease in adult offspring. Few studies, however, have examined the effects of maternal undernutrition on the vasculature of pregnant female offspring, and to our knowledge, no studies have examined myogenic responses, which are essential to vascular tone development, in these animal models. Thus, myogenic responses were assessed in radial uterine arteries of pregnant female offspring to determine if diet restriction during pregnancy could contribute to transgenerational effects. These results were compared to those in mesenteric arteries, which greatly contribute to peripheral vascular resistance. Myogenic responses in the presence and absence of inhibitors for nitric oxide synthase (NOS) and prostaglandin H synthase (PGHS) were measured in arteries isolated from pregnant, 3-mo-old female offspring of control-fed (C(off)) and globally diet-restricted (DR(off)) rat dams. Although no differences were found in pregnancy weight gain, litter size, or fetal weights, placental size was significantly reduced in DR(off) compared to C(off). Enhanced myogenic reactivity was observed at the highest pressure tested (110 mm Hg) in uterine, but not in mesenteric, arteries from DR(off) compared to C(off). Inhibition of NOS, but not of PGHS, significantly increased myogenic responses in uterine arteries at pressures greater than 80 mm Hg in C(off) but, interestingly, not in DR(off) compared to untreated uterine arteries. Thus, impaired uterine vascular function in diet-restricted pregnant rat dams, which leads to similar impairment in their pregnant offspring, may be a mechanism through which transgenerational effects of unhealthy pregnancies occur.

Animals↗
PubMed2004

Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions.

OBJECTIVE: Invasion of uterine spiral arteries by extravillous trophoblasts in the first trimester of pregnancy results in loss of endothelial and musculoelastic layers. This remodeling is crucial for an adequate blood supply to the fetus with a failure to remodel implicated in the etiology of the hypertensive disorder preeclampsia. The mechanism by which trophoblasts induce this key process is unknown. This study gives the first insights into the potential mechanisms involved. METHODS AND RESULTS: Spiral arteries were dissected from nonplacental bed biopsies obtained at Caesarean section, and a novel model was used to mimic in vivo events. Arteries were cultured with trophoblasts in the lumen, and apoptotic changes in the endothelial layer were detected after 20 hours, leading to loss of endothelium by 96 hours. In vitro, coculture experiments showed that trophoblasts stimulated apoptosis of primary decidual endothelial cells and an endothelial cell line. This was blocked by caspase inhibition and NOK2, a FasL blocking antibody. NOK2 also abrogated trophoblast-induced endothelial apoptosis in the vessel model. CONCLUSIONS: Extravillous trophoblast induction of endothelial apoptosis is a possible mechanism by which the endothelium is removed, and vascular remodeling may occur in uterine spiral arteries. Fas/FasL interactions have an important role in trophoblast-induced endothelial apoptosis.

Apoptosis↗
PubMed2004

Gender differences in myogenic tone in superoxide dismutase knockout mouse: animal model of oxidative stress.

Oxidative stress mediated by prooxidants has been implicated in the pathogenesis of vascular disorders. However, the effect of prooxidants on myogenic regulation of vascular function and the differential influence of gender is not known. SOD, an intracellular enzyme, restricts excess prooxidant levels and may limit vascular dysfunction. We therefore tested the effects of Cu,Zn SOD deficiency on vascular tone in both male and female SOD knockout (SOD-/-) mice. We hypothesized that myogenic tone would be enhanced in SOD-/- mice by excess prooxidants compared with wild-type control mice. Indeed, resistance-sized mesenteric arteries from SOD-/- mice exhibited enhanced myogenic tone compared with control mice. Myogenic tone was lower in female than male control mice. Interestingly, this gender effect was absent in SOD-/- mice, such that myogenic tone of mesenteric arteries from females was equated to that of arteries from males. Furthermore, the pathways that modulate myogenic tone were diverse. In both male and female control mice, inhibition of prostaglandin H synthase (PGHS) and nitric oxide synthase (NOS) pathways enhanced myogenic tone. In female SOD-/- mice, inhibition of PGHS and NOS pathways enhanced myogenic tone to a greater extent compared with control mice. Conversely, in male SOD-/- mice, NOS and PGHS inhibition did not alter tone and only inhibition of gap junctions enhanced myogenic tone. In conclusion, this study revealed enhanced myogenic tone in SOD-/- mice compared with control mice. Furthermore, Cu,Zn SOD deficiency particularly enhanced myogenic tone in female mice such that their vascular tone attained the level of male SOD-/- mice, possibly mediated by prooxidants.

Animals↗
PubMed2004

Fetal brain activity and hemodynamic response to a vibroacoustic stimulus.

Previous studies have demonstrated the practicality of using functional magnetic resonance imaging (fMRI) techniques to assess fetal brain activity. The purpose of this study was to compare the fetal hemodynamic response to that of the adult. Seventeen pregnant subjects, all of whom were at more than 36 weeks gestation were scanned while the fetus was exposed to a vibroacoustic stimulus. Thirteen adult subjects were scanned with an equivalent acoustic stimulus. Of the fetal subjects, two could not be analyzed due to technical problems, eight did not show significant activation, and seven showed significant activation. In all cases, activation was localized within the temporal region. Measures of fetal hemodynamic responses revealed an average time to peak (ttp) of 7.36 +/- 0.94 sec and an average percentage change of 2.67 +/- 0.93%. In contrast, activation was detected in 5 of 13 adults with an average ttp of 6.54 +/- 0.54 sec and an average percentage change of 1.02 +/- 0.40%. The measurement of changes in the fetal hemodynamic response may be important in assessing compromised pregnancies.

Acoustic Stimulation↗
PubMed2004

Altered cell kinetics in cultured placental villous explants in pregnancies complicated by pre-eclampsia and intrauterine growth restriction.

Placentae in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are characterized by morphological variations, apoptosis, and syncytial shedding, features that are linked to inappropriate oxygen and inflammatory cytokines. Cell turnover within the placenta is dynamic. In this study, these cellular events have been investigated longitudinally using a placental explant model. Intrinsic variations between normal (n = 14), PE (n = 16) and IUGR pregnancies (n = 11), and their responses to oxygen (3% and 17%) and exogenous tumour necrosis alpha (TNFalpha), were recorded. Placental explants were assessed for apoptotic morphology, immunolocalization of MIB-1 (a proliferation marker), lactate dehydrogenase (a necrosis marker), and human chorionic gonadotrophin (hCG, a marker of cytotrophoblast differentiation). Explants under TNFalpha and 17% O2 revealed progressive degeneration of syncytiotrophoblast (ST) followed by restoration of hCG, localized to newly differentiated cytotrophoblasts. This differentiation was significantly enhanced in PE and IUGR. Responses to 3% O2 were similar between groups: a sharp decline in hCG and failure to recover thereafter. Exaggerated cell death was recorded in PE and IUGR explants exposed to TNFalpha and 3% O2. All significant changes in apoptosis were confined to ST and stromal compartments. Enhanced cell death was predominantly apoptotic in PE and necrotic in IUGR. 3% O2 promoted cell proliferation in normal placentae but this response was not reciprocated in PE and IUGR. Elevated hCG in PE and IUGR explants may represent a placental predisposition to differentiation in vivo. In addition, the increased susceptibility of villous components to cell death, in the absence of stimulated proliferation, may provide a powerful mechanism for aberrant or adaptive placental cell turnover in utero.

Apoptosis↗
PubMed2004

Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries.

OBJECTIVE: In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia. Study design Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (N=22) or women with preeclampsia (N=24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664. RESULTS: Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from women with preeclampsia. CONCLUSION: A PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia, such that the behavior of these arteries approximates to those from normal women. These agents offer a potential therapeutic strategy for the management of preeclampsia.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Myogenic reactivity is enhanced in rat radial uterine arteries in a model of maternal undernutrition.

OBJECTIVES: The purpose of this study was to determine if maternal undernutrition during pregnancy altered myogenic tone in small radial uterine arteries. STUDY DESIGN: Myogenic tone of radial uterine arteries was studied from late pregnant rats (day 20) that were fed either ad libitum or globally restricted diet (moderately severe dietary restriction) throughout pregnancy. RESULTS: Myogenic tone was enhanced in the radial uterine arteries from the diet-restricted compared with the ad libitum group. Nitric oxide synthase inhibition enhanced myogenic tone in the arteries from the ad libitum group only. Prostaglandin H synthase inhibition had no effect on myogenic tone in either group. CONCLUSION: Diet restriction during pregnancy enhances myogenic tone in the radial uterine arteries partly as a result of impairment of the nitric oxide synthase pathway. Enhanced myogenic tone in turn may reduce uteroplacental blood flow and, thus, contribute to reduced birth weight, and lead to effects of fetal programming in utero that can have long-term consequences into adulthood.

Animals↗
PubMed2004

Vasoconstriction of small arteries isolated from the human placental chorionic plate in normal and compromised pregnancy.

Our aim was to compare placental chorionic plate small artery function in normal pregnancies and those complicated by preeclampsia and intrauterine growth restriction. In particular we wished to test the hypothesis that the constrictive potential of placental small arteries is modified in compromised pregnancy. Biopsies were obtained from term placentas from uncomplicated pregnancies and those affected by preeclampsia and intrauterine growth restriction. Small arteries from the chorionic plate were dissected free from surrounding tissue and studied using parallel wire myography. Placental small arteries developed maintained constrictions to arginine vasopressin and the thromboxane-mimetic U46619. Arterial maximal constriction was reduced in both preeclampsia and intrauterine growth restriction. This effect was agonist independent. In intrauterine growth restriction, placental small arteries showed decreased sensitivity to U46619 but not to arginine vasopressin. Human placental chorionic plate small artery vasoconstriction is significantly reduced in compromised pregnancy, a factor that may lead to altered blood flow within the fetoplacental circulation in these conditions.

Adult↗
PubMed2004

The influence of oxygen and tumor necrosis factor-alpha on the cellular kinetics of term placental villous explants in culture.

Explanted placental fragments may provide a more physiological in vitro model of component cell function than single cell isolates. We have characterized these fragments for cell turnover and have monitored responses from 14 normal placentas under conditions of exogenous TNFalpha and atypical oxygen concentrations (3% and 17%), conditions associated with abnormal pregnancy and an aberrant in utero environment. Explants were assessed for apoptotic morphology, immunolocalization of Mib-1 (a proliferation marker), caspase 3 activity (an apoptosis promoter), lactate dehydrogenase (a necrosis marker), and human chorionic gonadotrophin [hCG, a marker of cytotrophoblast (CT) differentiation]. Consistent with a reduction in hCG, explants under 17% O(2) (with and without TNFalpha) showed a progressive degeneration of syncytiotrophoblast (ST) (days 0-2) followed by a restoration of hCG (days 4-8) localized to newly differentiated but not syncytialized CTs. In 3% O(2), hCG showed the same initial decline but failed to recover thereafter. Proliferation dropped significantly in 17% O(2) but was restored and exaggerated sixfold in 3% O(2). All reductions in hCG were associated with cell death and caspase-3. Early apoptosis was linked with syncytial loss; later apoptosis (days 8-11) was localized to the non-ST. Prolonged exposure to TNFalpha (days 4-11) increased ST apoptosis and necrosis but 3% O(2) had no significant effect. These findings show that placental explants can accommodate many aspects of CT proliferation, differentiation, and ST apoptosis in culture. TNFalpha enhanced ST decline but 3% oxygen (compared with 17%) was associated with reduced CT differentiation and a strong shift towards proliferation. These outcomes may reflect previous morphological changes in compromised pregnancies and confirm a possible role for oxygen and TNFalpha in aberrant trophoblast turnover.

Apoptosis↗
PubMed2003

Nitric oxide protects human extravillous trophoblast cells from apoptosis by a cyclic GMP-dependent mechanism and independently of caspase 3 nitrosylation.

Apoptosis is thought to play an important regulatory role in placental development and inappropriate trophoblast apoptosis has been implicated in complications of pregnancy such as pre-eclampsia. Here we show that apoptosis of a human extravillous trophoblast-derived cell line (SGHPL-4) can be regulated by nitric oxide (NO). Nitric oxide produced exogenously by the addition of NO donors was able to delay or inhibit apoptosis induced by a combination of tumour necrosis factor alpha and actinomycin D and to suppress the activity of caspase 3. Treatment with hepatocyte growth factor (HGF) stimulated expression of the inducible isoform of NO synthase and was also able to protect SGHPL-4 cells from caspase 3 activation and apoptosis. The inhibition of basal NO production with NO synthase inhibitors was shown to sensitise cells to apoptotic stimuli and to reduce the level of endogenous caspase 3 nitrosylation. The anti-apoptotic effects of NO in these extravillous trophoblast cells appear to be mediated through the production of cyclic GMP as inhibitors of soluble guanylate cyclase inhibited the protective effect of both HGF and NO donors.

Apoptosis↗
PubMed2003

Fetal brain activity in response to a visual stimulus.

Previous studies have demonstrated the use of functional magnetic resonance imaging (fMRI) to assess fetal brain activity. To extend these studies, a fetal fMRI experiment using a visual stimulus has been performed at 0.5 T. This used a block fMRI paradigm with a bright, constant-intensity light source being shone at the maternal abdomen for 8 sec followed by 16 sec of darkness. This was repeated typically 40 times on nine subjects all of whom were greater than 36 weeks gestational age. Of these, one could not be analysed due to motion, three did not show significant activation, and five showed significant activation (P < 0.0085). In all cases, activation was localised within the frontal cortex. Exact localisation was difficult but this may correspond to the frontal eye fields and dorsolateral prefontal cortex. In no cases was significant activation present within the occipital region as would have been expected and was observed in 2/8 adult subjects. Hum. Brain Mapping 20:239-245, 2003.

Brain↗
PubMed2003

Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction.

Placental apoptosis is increased in vivo in preeclampsia (PE) and intrauterine growth restriction (IUGR). The cause and pathological implications of this phenomenon are unknown. This study considers the apoptotic susceptibility of villous trophoblasts from normal, PE, and IUGR pregnancies. Cultured cytotrophoblasts (CTs) and an in vitro model of syncytialization were used. CTs were isolated from term placentas of 12 normal, 12 PE, and 12 IUGR pregnancies. Apoptosis was determined by terminal dUTP nick-end labeling (TUNEL), Annexin V binding, and ADP:ATP ratios. Cells were stimulated with tumor necrosis factor-alpha/interferon-gamma or reduced oxygen (<5 KPa). For CTs, ADP:ATP <1 correlates with Annexin V binding. For normal pregnancy, tumor necrosis factor-alpha and depleted oxygen significantly increased TUNEL, Annexin V binding and ADP:ATP in CTs and syncytiotrophoblasts (STs). Spontaneous apoptosis was similar between groups for both cell types. After stimulation, TUNEL and Annexin V binding of CTs were significantly raised in PE and IUGR as compared with normal pregnancy. After oxygen reduction, ADP:ATP in CTs and STs were significantly elevated in IUGR. TUNEL was also increased in STs in PE after oxygen depletion and was significantly raised in STs from IUGR pregnancies after stimulation with both agonists. This is the first description of enhanced apoptosis in isolated villous trophoblasts in PE and IUGR. These intrinsic differences may represent an important factor in the pathophysiology of these conditions.

Adenosine Diphosphate↗
PubMed2003

Vasoactive effects of neurokinin B on human blood vessels.

OBJECTIVES: Preeclampsia (PE) is a multisystem disease unique to human pregnancy. Abnormal placentation results in placental hypoperfusion leading to the secretion of a factor(s) by the placenta. Our aim was to investigate whether neurokinin B (NKB) is the circulating factor associated with PE. STUDY DESIGN: Vascular effects of NKB were assessed in blood vessels dissected from myometrial and omental biopsy specimens obtained at caesarean section from normal pregnant women (n = 26) or in mesenteric blood vessels obtained from nonpregnant female Wistar rats (n = 4). RESULTS: Incubation with NKB did not alter endothelial-dependent relaxation of omental or myometrial arteries. NKB produced a dose-dependent relaxation in preconstricted omental arteries and veins. NKB did not affect vasoactive responsiveness of rat mesenteric arteries. CONCLUSION: We conclude from these observations that NKB is not the circulating factor associated with increased vascular resistance in PE.

Animals↗
PubMed2003

The receptor for advanced glycation end products (RAGE) is elevated in women with preeclampsia.

A leading theory of the pathophysiology of preeclampsia is that oxidative stress induces vascular endothelial cell dysfunction. Advanced glycation end products (AGEs) form when aldose sugars react nonenzymatically with proteins under conditions of oxidative stress. AGEs are circulating molecules and can generate reactive oxygen species and vascular dysfunction (in diabetes and atherosclerosis) through an association with cell surface receptors (RAGE). RAGE is a multiligand receptor, expressed in vascular tissue, which is upregulated by its own ligands. Insulin resistance and obesity are risk factors for developing preeclampsia, as well as being conditions that would increase RAGE levels. Thus, we hypothesized that women with preeclampsia will have elevated levels of RAGE protein compared with normal pregnant women. Biopsies of nonlaboring myometrium as well as omentum were taken from normal pregnant and preeclamptic women. Nonpregnant samples were obtained at the time of hysterectomy. Tissue sections were immunostained with anti-RAGE as well as anti-alpha-actin and anti-von Willebrand factor (to identify blood vessels and intact endothelial cells). Staining intensity was qualitatively described as well as given an intensity score, with the identity of the section concealed. Nonpregnant myometrial and omental vessels showed very low to undetectable levels of RAGE staining. Pregnancy induced a significant increase in RAGE protein levels in both myometrium and omental vasculature. Blood vessels from women with preeclampsia consistently had intense staining for RAGE in both vessel beds. Thus, our data suggest that since RAGE activation can induce similar pathophysiologic changes to those observed in women with preeclampsia (including NFkappaB activation, increased TNFalpha and endothelin), elevated RAGE protein may be contributing to the vascular dysfunction in preeclampsia.

Adult↗