Management of obesity across women's life course: FIGO Best Practice Advice.

Obesity is a chronic, progressive, relapsing, and treatable multifactorial, neurobehavioral disease. According to the World Health Organization, obesity affects 15% of women and has long-term effects on women's health. The focus of care in patients with obesity should be on optimizing health outcomes rather than on weight loss. Appropriate and common language, considering cultural sensitivity and trauma-informed care, is needed to discuss obesity. Pregnancy is a time of significant physiological change. Pre-, ante-, and postpartum clinical encounters provide opportunities for health optimization for parents with obesity in terms of, but not limited to, fertility and breastfeeding. Pre-existing conditions may also be identified and managed. Beyond pregnancy, women with obesity are at an increased risk for gastrointestinal and liver diseases, impaired kidney function, obstructive sleep apnea, and venous thromboembolism. Gynecological and reproductive health of women living with obesity cannot be dismissed, with accommodations needed for preventive health screenings and consideration of increased risk for gynecologic malignancies. Mental wellness, specifically depression, should be screened and managed appropriately. Obesity is a complex condition and is increasing in prevalence with failure of public health interventions to achieve significant decrease. Future research efforts should focus on interprofessional care and discovering effective interventions for health optimization.

Repeated truncation of a modular antimicrobial peptide gene for neural context.

Antimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading pathogens. These genes commonly encode multiple products as post-translationally cleaved polypeptides. Recent studies have highlighted roles for AMPs in neurological contexts suggesting functions for these defence molecules beyond infection. During our immune study characterizing the antimicrobial peptide gene Baramicin, we recovered multiple Baramicin paralogs in Drosophila melanogaster and other species, united by their N-terminal IM24 domain. Not all paralogs were immune-induced. Here, through careful dissection of the Baramicin family's evolutionary history, we find that paralogs lacking immune induction result from repeated events of duplication and subsequent truncation of the coding sequence from an immune-inducible ancestor. These truncations leave only the IM24 domain as the prominent gene product. Surprisingly, using mutation and targeted gene silencing we demonstrate that two such genes are adapted for function in neural contexts in D. melanogaster. We also show enrichment in the head for independent Baramicin genes in other species. The Baramicin evolutionary history reveals that the IM24 Baramicin domain is not strictly useful in an immune context. We thus provide a case study for how an AMP-encoding gene might play dual roles in both immune and non-immune processes via its multiple peptide products. As many AMP genes encode polypeptides, a full understanding of how immune effectors interact with the nervous system will require consideration of all their peptide products.

Longitudinal dietary trajectories from preconception to mid-childhood in women and children in the Southampton Women's Survey and their relation to offspring adiposity: a group-based trajectory modelling approach.

BACKGROUND: Rates of childhood obesity are increasing globally, with poor dietary quality an important contributory factor. Evaluation of longitudinal diet quality across early life could identify timepoints and subgroups for nutritional interventions as part of effective public health strategies. OBJECTIVE: This research aimed to: (1) define latent classes of mother-offspring diet quality trajectories from pre-pregnancy to child age 8-9 years, (2) identify early life factors associated with these trajectories, and (3) describe the association between the trajectories and childhood adiposity outcomes. DESIGN: Dietary data from 2963 UK Southampton Women's Survey mother-offspring dyads were analysed using group-based trajectory modelling of a diet quality index (DQI). Maternal diet was assessed pre-pregnancy and at 11- and 34-weeks' gestation, and offspring diet at ages 6 and 12 months, 3, 6-7- and 8-9-years using interviewer-administered food frequency questionnaires. At each timepoint, a standardised DQI was derived using principal component analysis. Adiposity age 8-9 years was assessed using dual-energy X-ray absorptiometry (DXA) and BMI z-scores. RESULTS: A five-trajectory group model was identified as optimal. The diet quality trajectories were characterised as stable, horizontal lines and were categorised as poor (n = 142), poor-medium (n = 667), medium (n = 1146), medium-better (n = 818) and best (n = 163). A poorer dietary trajectory was associated with higher maternal pre-pregnancy BMI, smoking, multiparity, lower maternal age and lower educational attainment. Using linear regression adjusted for confounders, a 1-category decrease in the dietary trajectory was associated with higher DXA percentage body fat (0.08 SD (95% confidence interval 0.01, 0.15) and BMI z-score (0.08 SD (0.00, 0.16) in the 1216 children followed up at age 8-9 years. CONCLUSION: Mother-offspring dietary trajectories are stable across early life, with poorer diet quality associated with maternal socio-demographic and other factors and childhood adiposity. The preconception period may be an important window to promote positive maternal dietary changes in order to improve childhood outcomes.

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

Maternal Factors Are Associated with the Expression of Placental Genes Involved in Amino Acid Metabolism and Transport.

INTRODUCTION: Maternal environment and lifestyle factors may modify placental function to match the mother's capacity to support the demands of fetal growth. Much remains to be understood about maternal influences on placental metabolic and amino acid transporter gene expression. We investigated the influences of maternal lifestyle and body composition (e.g. fat and muscle content) on a selection of metabolic and amino acid transporter genes and their associations with fetal growth. METHODS: RNA was extracted from 102 term Southampton Women's Survey placental samples. Expression of nine metabolic, seven exchange, eight accumulative and three facilitated transporter genes was analyzed using quantitative real-time PCR. RESULTS: Increased placental LAT2 (p = 0.01), y+LAT2 (p = 0.03), aspartate aminotransferase 2 (p = 0.02) and decreased aspartate aminotransferase 1 (p = 0.04) mRNA expression associated with pre-pregnancy maternal smoking. Placental mRNA expression of TAT1 (p = 0.01), ASCT1 (p = 0.03), mitochondrial branched chain aminotransferase (p = 0.02) and glutamine synthetase (p = 0.05) was positively associated with maternal strenuous exercise. Increased glutamine synthetase mRNA expression (r = 0.20, p = 0.05) associated with higher maternal diet quality (prudent dietary pattern) pre-pregnancy. Lower LAT4 (r = -0.25, p = 0.05) and aspartate aminotransferase 2 mRNA expression (r = -0.28, p = 0.01) associated with higher early pregnancy diet quality. Lower placental ASCT1 mRNA expression associated with measures of increased maternal fat mass, including pre-pregnancy BMI (r = -0.26, p = 0.01). Lower placental mRNA expression of alanine aminotransferase 2 associated with greater neonatal adiposity, for example neonatal subscapular skinfold thickness (r = -0.33, p = 0.001). CONCLUSION: A number of maternal influences have been linked with outcomes in childhood, independently of neonatal size; our finding of associations between placental expression of transporter and metabolic genes and maternal smoking, physical activity and diet raises the possibility that their effects are mediated in part through alterations in placental function. The observed changes in placental gene expression in relation to modifiable maternal factors are important as they could form part of interventions aimed at maintaining a healthy lifestyle for the mother and for optimal fetal development.

Polyunsaturated fatty acid biosynthesis is involved in phenylephrine-mediated calcium release in vascular smooth muscle cells.

Stimulation of vascular smooth muscle (VSM) α1-adrenoceptors induces myosin phosphorylation and vasoconstriction via mobilisation of intracellular calcium and production of specific eicosanoids. Polyunsaturated fatty acid (PUFA) biosynthesis in VSM cells is involved, although the precise mechanism is not known. To address this, we characterised PUFA biosynthesis in VSM cells and determined its role in intracellular calcium release and eicosanoid production. Murine VSM cells converted 18:2n-6 to longer chain PUFA including 22:5n-6. Δ6 (D6d) and Δ5 (D5d) desaturase, and elongase (Elovl) 5 were expressed. Elovl2 was not detected in human, mouse or rat VSM cells, or in rat or mouse aortae, but tit was not associated with hypermethylation of its promoter. D6d or D5d inhibition reduced 18:3n-6 and 20:4n-6 synthesis, respectively, and induced concentration-related decrease in phenylephrine-mediated calcium release, and in PGE2 and PGF2α secretion. Together these findings suggest that PUFA biosynthesis in VSM cells is involved in calcium release associated with vasoconstriction.

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast.

The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter-ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter-ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans-stimulated by an OAT4 and OATP2B1 substrate (bromosulphothalein). Exchange of glutamate for bromosulphothalein was only observed when glutamate reuptake was inhibited (by addition of aspartate). To determine if OAT4 and/or OATP2B1 mediate glutamate exchange, uptake and efflux of glutamate were investigated in Xenopus laevis oocytes. Our data demonstrate that in Xenopus oocytes expressing either OAT4 or OATP2B1 efflux of intracellular [(14)C]glutamate could be stimulated by conditions including extracellular glutamate (OAT4), estrone-sulphate and bromosulphothalein (both OAT4 and OATP2B1) or pravastatin (OATP2B1). Cycling of glutamate across the placenta involving efflux via OAT4 and OATP2B1 and subsequent reuptake will drive placental uptake of organic anions from the fetal circulation.

Tissue-specific 5' heterogeneity of PPARα transcripts and their differential regulation by leptin.

The genes encoding nuclear receptors comprise multiple 5'untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors.

Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring.

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18 % casein) or an isocaloric low-protein diet throughout gestation (LPD; 9 % casein), or fed the LPD exclusively during the pre-implantation period (3.5 d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P = 0.04 and P = 0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na+/K+ ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P = 0.044), whilst Emb-LPD males had elevated lung ACE activity (P = 0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected.

Atorvastatin restores endothelial function in offspring of protein-restricted rats in a cholesterol-independent manner.

Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO(2) inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (P<0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (P<0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and beta(2)-microglobulin in male and C-reactive protein in female offspring (P<0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (P<0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-alpha were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed.

Endothelial dysfunction and reduced antioxidant protection in an animal model of the developmental origins of cardiovascular disease.

Endothelial dysfunction underlies cardiovascular disease (CVD) in humans and is reported in animal models of developmental origins of such disease. We have investigated whether impaired antioxidant defences and NO generation underlie the genesis of endothelial dysfunction and operate as part of the normal processes of developmental plasticity regulating the induction of phenotype in the offspring. Female Wistar rats were fed either a control (C, 18% protein) or protein-restricted (PR, 9% protein) diet throughout pregnancy. Dams and pups were returned to standard laboratory chow post partum. In male offspring, PR resulted in a reduced endothelial responsiveness to acetylcholine (P < 0.05) in resistance arteries, with vascular remodelling evident from a reduction in smooth muscle content. mRNA expression of endothelial NO synthase (eNOS) was increased (P < 0.05) but there was no change in mRNA levels of manganese superoxide dismutase (MnSOD) or glutamate cysteine ligase (GCL) expression. Interestingly, expression of the antioxidant enzyme haem oxygenase-1 (HO-1) was reduced in the liver (P < 0.05). Female PR offspring also showed a reduced endothelial responsiveness but exhibited no changes in expression of eNOS, iNOS, soluble guanylate cyclase (sGC) or antioxidant genes. Thus, in this model of the developmental origins of CVD, the structure and function of resistance arteries in offspring is altered in complex ways which cannot simply be explained by attenuation in vascular eNOS or in antioxidant protection afforded by GCL or MnSOD. The dysfunction in male offspring may partially be counteracted by an up-regulation of eNOS expression; however, PR does lead to reduced HO-1 expression in these offspring, which may affect both their growth and vascular function. Our findings have established that PR induces significant phenotypic changes in male offspring that may be indicative of an adaptive response during development.

Metabolic plasticity during mammalian development is directionally dependent on early nutritional status.

Developmental plasticity in response to environmental cues can take the form of polyphenism, as for the discrete morphs of some insects, or of an apparently continuous spectrum of phenotype, as for most mammalian traits. The metabolic phenotype of adult rats, including the propensity to obesity, hyperinsulinemia, and hyperphagia, shows plasticity in response to prenatal nutrition and to neonatal administration of the adipokine leptin. Here, we report that the effects of neonatal leptin on hepatic gene expression and epigenetic status in adulthood are directionally dependent on the animal's nutritional status in utero. These results demonstrate that, during mammalian development, the direction of the response to one cue can be determined by previous exposure to another, suggesting the potential for a discontinuous distribution of environmentally induced phenotypes, analogous to the phenomenon of polyphenism.

Does estrogen affect the development of abnormal vascular function in offspring of rats fed a low-protein diet in pregnancy?

It is established that there are gender-related differences in the effects on offspring blood pressure induced by maternal protein restriction in animal studies. Since such effects may depend on estrogen levels, we hypothesized that lower estrogen would induce an earlier onset of hypertension caused by maternal under-nutrition. Wistar rats were fed a diet containing either 18% (C) or 9% (R) casein throughout pregnancy. Half of the offspring in both C and R groups were ovariectomized on day 50 (CX, RX), and the other half underwent a sham operation (CO, RO). On d 175, offspring were killed for small artery reactivity and histologic investigation. Birth weight and later growth were not significantly different between C and R. RX had higher systolic blood pressure than CX on d125, but no difference was seen between RO and CO. On d 175, systolic blood pressure was higher in R than in C, whether or not ovariectomized. Dilator responses to acetylcholine and bradykinin in small mesenteric arteries were significantly attenuated in RX, although responses to SNP and isoprenaline showed no attenuation in R. The ratio of coronary peri-vascular fibrosis to total vascular area was higher in R, and the fibrosis became prominent in ovariectomized rats. These findings suggest that estrogen plays an important role in limiting the elevation of offspring blood pressure induced by maternal under-nutrition, possibly via BK-mediated mechanisms. The processes may underlie gender and life course patterns of hypertension and also the developmental origins of this disease.

Effects of pre-natal and early post-natal undernutrition on adult internal thoracic artery function.

OBJECTIVE: Previous studies in humans and animals have suggested that undernutrition in utero and in early post-natal life may lead to altered vascular function in a number of peripheral arteries. We investigated the effect of pre- and post-natal nutrient restriction on the vascular reactivity of the left internal thoracic artery using a sheep model. METHODS: Welsh mountain ewes were mated and assigned to three dietary groups: (1) 100% of total nutritional requirements (control, n=6); (2) 50% of total nutritional requirements during the first 31 days of gestation (n=6); and (3) 50% nutritional restriction during the first 31 days of gestation, followed by a restriction in the diet of their offspring 12-25 weeks post-natally, designed to produce a 15% reduction in growth trajectory (n=7). The male offspring were sacrificed at 130 weeks; the left internal thoracic artery was mounted onto a wire myograph and the reactivity of the vessel to various agonists measured. RESULTS: The offspring of animals who underwent an early gestation nutrient restriction had a significantly increased basal tone (0.41+/-0.25 vs 6.34+/-1.35, p=0.015) and sensitivity to phenylephrine (log EC(50): -6.23+/-0.04 M vs -5.74+/-0.17 M, p=0.036) as compared with control animals. However, this phenomenon was not seen in animals that underwent both pre- and post-natal nutrient restriction. CONCLUSIONS: Pre-natal undernutrition increases the basal tone and sensitivity of the left internal thoracic artery to phenylephrine. This effect is significantly attenuated by continued undernutrition in early post-natal life. These experiments suggest that in utero and early post-natal undernutrition may be important determinants of graft function in later life.

Fetal origins of coronary heart disease-implications for cardiothoracic surgery?

Over the last 15 years, there has been growing evidence that poor nutrition during gestation plays an important role in the development of coronary heart disease. This hypothesis, commonly known as the 'fetal origins of adult disease' has now gained widespread acceptance in the scientific community. In this review, we discuss the evidence for this theory and analyse the patho-physiological mechanisms underlying the relationship between altered fetal growth and coronary heart disease. Finally, the potential relevance of the theory to cardiac surgical practice will be evaluated.

The effect of dietary supplementation with linoleic acid to late gestation ewes on the fatty acid composition of maternal and fetal plasma and tissues and the synthetic capacity of the placenta for 2-series prostaglandins.

Linoleic acid (18:2n-6) is metabolised to arachidonic acid (20:4n-6), the precursor for 2-series prostaglandins (PGs). Increased consumption of 18:2n-6 during pregnancy may thus modify PG synthesis during labour. We have investigated whether increased 18:2n-6 composition during gestation altered the fatty acid consumption and PG synthesis of maternal and fetal tissues in the sheep. Ewes were fed a control diet or a diet providing 40% more 18:2n-6 from 96 days gestation. Half of each group received dexamethasone on day 136 to up-regulate the PG synthetic pathways promoting parturition. Maternal and fetal tissues were collected at 138 days. The 18:2n-6 diet significantly increased the 20:4n-6 content of maternal plasma, fetal plasma and allantochorion (51-81%) phosphatidylcholine, and fetal liver (40%) and maternal caruncular endometrium (57%) phosphatidylethanolamine. Increased 18:2n-6 intake increased production of PGF(2alpha) and PGE(2) in all placental tissues (maternal caruncular and intercaruncular endometrium and fetal allantochorion) by 23-98%, whereas dexamethasone increased it by 32-142%. This suggests that consumption of an 18:2n-6-enriched diet in late pregnancy enhanced placental PG production by increasing the supply of 20:4n-6. Variations in the extent to which the diet altered the polyunsaturated fatty acid (PUFA) content of the different tissues indicated complex interactions between nutrient availability and metabolic adaptation.

Effect of nutritional restriction in early pregnancy on isolated femoral artery function in mid-gestation fetal sheep.

Unbalanced maternal nutrition affects fetal endocrine and cardiovascular systems, sometimes accompanied by changes in growth, although this is usually in late gestation. We determined the effect of moderate restriction for the first half of gestation of maternal dietary protein, or of total calorific intake on isolated resistance artery function of mid-gestation fetal sheep. Welsh Mountain ewes were nutritionally restricted by 30 % of the recommended nutrient intake (globally restricted) or 30 % of the recommended protein intake (protein-restricted), compared to control ewes fed 100 % of recommended nutrient intake, for ~12 days prior to conception and for the subsequent 70 days of gestation. At mid-gestation, fetal and placental weights were similar in all dietary groups. In isolated femoral arteries, the response curve to noradrenaline was reduced in protein-restricted group fetuses (P < 0.05). Maximal relaxation (P < 0.01) and sensitivity (P < 0.05) to acetylcholine were markedly reduced in protein-restricted group fetuses, and to a smaller extent in globally restricted group fetuses (response curve, P < 0.05). The dilator response (P < 0.05) and sensitivity (P < 0.05) to the alpha2 agonist UK14304 was lower in protein-, but not in globally restricted group fetuses. The response (P < 0.05) and sensitivity (P < 0.05) to the nitric oxide donor sodium nitroprusside were reduced in protein-restricted group fetuses compared to controls. Our data show that dietary imbalance, in particular restricted protein, of the ewe can produce blunting of endothelial-dependent and -independent relaxation in systemic arteries from the mid-gestation fetus. These changes may precede perturbed late-gestation fetal and postnatal cardiovascular control.

The effect of systemic administration of lipopolysaccharide on cerebral haemodynamics and oxygenation in the 0.65 gestation ovine fetus in utero.

OBJECTIVE: To investigate the effect of intravenous lipopolysaccharide on systemic and cerebral haemodynamics and oxygenation in the preterm ovine fetus. DESIGN: Prospective observational study. SETTING: Research centre for perinatal brain injury. SAMPLE: Nine fetal sheep at circa 93 days of gestation (0.65). METHODS: Fetal sheep were chronically instrumented with arterial and venous catheters and a flow probe in the carotid artery. Near-infrared spectroscopy was used to measure changes in cerebral oxygenation and total haemoglobin concentration. Three days after surgery, each fetus was given 100 ng/kg Escherichia coli lipopolysaccharide. Observations were continued for 48 hours post-injection and compared with baseline control values. MAIN OUTCOME MEASURES: Fetal heart rate, mean arterial pressure, carotid blood flow. RESULTS: Three fetuses died after administration of the lipopolysaccharide. In the survivors fetal heart rate rose from 193 (SEM 7) to a mean maximal level of 226 (SEM 31 bpm) (P = 0.01) after 6.5 (SEM 1.0) hours. The mean arterial pressure decreased from 40.5 (SEM 4.2) to 29.4 (SEM 1.6) mmHg (P < 0.05) after 7.0 (SEM 2.0) hours, and carotid blood flow increased from 29.6 (SEM 1.6) to 45.8 (SEM 5.7) mL/min (P = 0.0002) at 12 (SEM 3) hours. All values returned to control levels by 48 hours. Histological assessment showed evidence of periventricular leucomalacia in three out of six brains studied. CONCLUSION: These data do not suggest that cerebral ischaemia is the main aetiological factor in endotoxin-related fetal brain injury. Fetal tachycardia and cerebral vasodilation may indicate endotoxaemia in fetuses exposed to prenatal infection.

Vasodilation to vascular endothelial growth factor in the uterine artery of the pregnant rat is blunted by low dietary protein intake.

Pregnancy is associated with a substantial increase in uterine artery blood flow, which may in part result from dilation in response to vascular endothelial growth factor (VEGF). Uterine blood flow is reported to be reduced in globally diet-restricted pregnant rats. Both global and protein dietary restriction in pregnancy produce programmed effects in offspring. In this study we hypothesized that protein restriction in pregnancy impairs maternal uterine artery responses to VEGF. Vascular responses to VEGF were determined in isolated uterine arteries of pregnant (18 or 19 d of gestation) Wistar rats fed a diet containing either 18% or 9% casein throughout pregnancy. For comparison, responses to phenylephrine, potassium chloride, and acetylcholine were determined. In addition, the response of the mesenteric artery to VEGF was studied in the same animals. A significant reduction of the maximal relaxation to VEGF (p = 0.041) and in the overall response (p = 0.004) to VEGF was found in uterine arteries of the 9% compared with the 18% group, but responses to all other agonists were similar. The VEGF response was reduced by cyclooxygenase inhibition (indomethacin) in both groups. In the 18%, but not the 9%, group it was further reduced by nitric oxide synthase inhibition (Nomega-nitro-L-arginine methyl ester). VEGF was shown to dilate the mesenteric artery but this effect was not significantly altered by the low-protein diet. These results show an attenuated uterine artery vasodilator response to VEGF produced by a low-protein diet in pregnancy, partly because of a reduction of the nitric oxide component of VEGF-mediated relaxation.