Epigenetics and developmental programming of welfare and production traits in farm animals.

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the 'developmental origins of health and disease' or 'DOHaD' hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems.

Indices of adiposity as predictors of cardiometabolic risk and inflammation in young adults.

BACKGROUND: Studies investigating obesity and cardiometabolic risk have focused on 'at-risk' populations and methodological inconsistencies have produced equivocal findings. The present cross-sectional study investigated indices of body composition as predictors of cardiometabolic risk and their relationship with inflammation in apparently healthy young adults. METHODS: A fasting blood sample was taken from consenting adults (160 males, 32 females, aged 18-40 years) for assessment of cardiometabolic risk markers (blood pressure, lipid profiles and insulin resistance) and inflammatory markers (C-reactive protein, tumour necrosis factor-α, interleukin-6, interleukin-10 and adiponectin). Together with anthropometry, fat mass (FM) and fat-free mass (FFM) were determined by dual-energy X-ray absorptiometry. FM was expressed in absolute terms (kg), as well as relative to total body weight (%), height [FM index (FMI, kg m(-2) )] and FFM (FM : FFM,%). RESULTS: Although anthropometric indices were associated with most cardiometabolic risk markers, the strongest relationship was observed with FMI. Relative to having a low cardiometabolic risk (≤2 markers above clinically relevant cut-offs), each kg m(-2) increase in FMI, increased the likelihood of having an increased cardiometabolic risk by 29% (odds ratio = 1.29; 95% confidence interval = 1.12-1.49). Inflammatory markers were not associated with body composition or cardiometabolic risk. CONCLUSIONS: FMI was the strongest predictor of overall cardiometabolic risk but not inflammation per se. However, anthropometric indices, such as body mass index and waist-to-height ratio, remain valuable surrogate measures of adiposity in this group, particularly when risk markers are considered independently.

Perceived 'healthiness' of foods can influence consumers' estimations of energy density and appropriate portion size.

OBJECTIVE: To compare portion size (PS) estimates, perceived energy density (ED) and anticipated consumption guilt (ACG) for healthier vs standard foods. METHODS: Three pairs of isoenergy dense (kJ per 100 g) foods-healthier vs standard cereals, drinks and coleslaws-were selected. For each food, subjects served an appropriate PS for themselves and estimated its ED. Subjects also rated their ACG about eating the food on a scale of 1 (not at all guilty) to 5 (very guilty). RESULTS: Subjects (n=186) estimated larger portions of the healthier coleslaw than that of the standard version, and perceived all healthier foods to be lower in ED than their standard alternatives, despite being isoenergy dense. Higher ACG was associated with the standard foods. Portion estimates were generally larger than recommendations and the ED of the foods was underestimated. CONCLUSIONS: The larger portions selected for the 'reduced fat' food in association with lower perceived ED and ACG suggests that such nutrition claims could be promoting inappropriate PS selection and consumption behaviour. Consumer education on appropriate portions is warranted to correct such misconceptions.

A case of successful pregnancy in a ewe with uterus didelphys.

Uterus didelphys is a rare congenital abnormality of the reproductive tract. Although it occurs in various species, there are no published reports describing pregnancy outcome in association with this abnormality. Herein we describe a case of successful unilateral singleton pregnancy in a ewe incidentally found to have uterus didelphys during the course of a biomedical research study. The pregnancy was established using assisted reproductive techniques and interrupted in late gestation, at which point the abnormality was identified. Serial ultrasound assessment of foetal biometry revealed a normal foetal growth trajectory. Despite a 45% reduction in placentome number, total placentome weight was near normal secondary to compensatory placentome growth and development. To our knowledge, this is the first detailed report of normal foetal growth in an animal with uterus didelphys and illustrates the ability of the ovine placenta to adapt to a reduced number of placentomes and maintain foetal nutrient supply.

Red meat from animals offered a grass diet increases plasma and platelet n-3 PUFA in healthy consumers.

Red meat from grass-fed animals, compared with concentrate-fed animals, contains increased concentrations of long-chain (LC) n-3 PUFA. However, the effects of red meat consumption from grass-fed animals on consumer blood concentrations of LC n-3 PUFA are unknown. The aim of the present study was to compare the effects on plasma and platelet LC n-3 PUFA status of consuming red meat produced from either grass-fed animals or concentrate-fed animals. A randomised, double-blinded, dietary intervention study was carried out for 4 weeks on healthy subjects who replaced their habitual red meat intake with three portions per week of red meat (beef and lamb) from animals offered a finishing diet of either grass or concentrate (n 20 consumers). Plasma and platelet fatty acid composition, dietary intake, blood pressure, and serum lipids and lipoproteins were analysed at baseline and post-intervention. Dietary intakes of total n-3 PUFA, as well as plasma and platelet concentrations of LC n-3 PUFA, were significantly higher in those subjects who consumed red meat from grass-fed animals compared with those who consumed red meat from concentrate-fed animals (P < 0·05). No significant differences in concentrations of serum cholesterol, TAG or blood pressure were observed between groups. Consuming red meat from grass-fed animals compared with concentrate-fed animals as part of the habitual diet can significantly increase consumer plasma and platelet LC n-3 PUFA status. As a result, red meat from grass-fed animals may contribute to dietary intakes of LC n-3 PUFA in populations where red meat is habitually consumed.

Vitamin D status and parathyroid hormone relationship in adolescents and its association with bone health parameters: analysis of the Northern Ireland Young Heart's Project.

UNLABELLED: In girls, a plateau in parathyroid hormone (PTH) was observed at a 25-hydroxyvitamin D (25(OH)D) concentration of approximately 60 nmol/l. In boys, there was no plateau in PTH concentrations as 25(OH)D concentration increased. A 25(OH)D threshold of 60 nmol/l appears to have implications for bone health outcomes in both girls and boys. INTRODUCTION: Our objective was to investigate if there is a threshold 25(OH)D concentration where a plateau in PTH concentration is evident and to examine the impact of this relationship on bone mineral density (BMD) and bone turnover in a representative sample of adolescents. METHODS: We conducted a cross-sectional analysis among 1,015 Northern Irish adolescents aged 12 and 15 years. Serum 25(OH)D, PTH, osteocalcin, type 1 collagen cross-linked C-telopeptide (CTx), and BMD of the nondominant forearm and heel were measured. Nonlinear regression analysis was used to model the association between 25(OH)D and PTH. RESULTS: In girls, a plateau in PTH was observed at a 25(OH)D concentration of approximately 60 nmol/l (PTH = 47.146 + 370.314 x exp((-0.092 x 25(OH)D))) while no plateau in PTH was observed in boys (PTH = 42.144 + 56.366 x exp((-0.022 x 25(OH)D))). Subjects with 25(OH)D levels <60 nmol/l had significantly higher osteocalcin concentrations (P < 0.05) compared with those who had >or=60 nmol/l, while no significant (P > 0.05) differences were noted for CTx concentrations. In girls only, nondominant forearm BMD but not heel BMD was significantly higher (P = 0.046) in those with 25(OH)D concentrations >or= 60 nmol/l. CONCLUSIONS: Serum 25(OH)D levels above 60 nmol/l in Northern Irish adolescent girls prevent an increase in serum PTH levels and maintaining 25(OH)D >60 nmol/l in both girls and boys may lead to improved bone health outcomes.

Meteorological aspects of the el nino/southern oscillation.

The single most prominent signal in year-to-year climate variability is the Southern Oscillation, which is associated with fluctuations in atmospheric pressure at sea level in the tropics, monsoon rainfall, and wintertime circulation over North America and other parts of the extratropics. Although meteorologists have known about the Southern Oscillation for more than a half-century, its relation to the oceanic El Niño phenomenon was not recognized until the late 1960's, and a theoretical understanding of these relations has begun to emerge only during the past few years. The past 18 months have been characterized by what is probably the most pronounced and certainly the best-documented El Niño/Southern Oscillation episode of the past century. In this review meteorological aspects of the time history of the 1982-1983 episode are described and compared with a composite based on six previous events between 1950 and 1975, and the impact of these new observations on theoretical interpretations of the event is discussed.

Regional climate impacts of the Northern Hemisphere annular mode.

The Northern Hemisphere annular mode (NAM) (also known as the North Atlantic Oscillation) is shown to exert a strong influence on wintertime climate, not only over the Euro-Atlantic half of the hemisphere as documented in previous studies, but over the Pacific half as well. It affects not only the mean conditions, but also the day-to-day variability, modulating the intensity of mid-latitude storms and the frequency of occurrence of high-latitude blocking and cold air outbreaks throughout the hemisphere. The recent trend in the NAM toward its high-index polarity with stronger subpolar westerlies has tended to reduce the severity of winter weather over most middle- and high-latitude Northern Hemisphere continental regions.

The relationship between gender and age with monocyte tissue factor expression.

BACKGROUND: In normal healthy individuals, the level of tissue factor (TF) expression on monocytes is low. However, studies have shown that patients with cardiovascular disease (CVD) have elevated levels of TF. As the risk of CVD increases with age and is more prominent in the male population, it is postulated that TF expression may be positively correlated with these factors. However, very few studies have examined the relationship between age and gender on TF expression. METHODS: This study evaluated the influence of age and gender on TF expression using data obtained from female (n = 44) and male (n = 27) subjects. We also examined the influence of BMI and total fat intake on TF expression in the same subjects. RESULTS: The results of our study found no significant difference in TF expression between the male and female subgroups. No correlation was found between TF and age, BMI or total fat intake in the male or female groupings. CONCLUSION: It may be postulated that the risk of CVD development in such populations may not be due to increases in TF expression with increasing age or gender differences.

Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors.

OBJECTIVE: To investigate the relative efficacy of four popular weight-loss programmes on plasma lipids and lipoproteins as measures of CVD risk. DESIGN: A multi-centred, randomised, controlled trial of four diets - Dr Atkins' New Diet Revolution, The Slim-Fast Plan, Weight Watchers Pure Points programme and Rosemary Conley's 'Eat yourself Slim' Diet and Fitness Plan - against a control diet, in parallel for 6 months. SETTING AND SUBJECTS: The trial was conducted at five universities across the UK (Surrey, Nottingham, Ulster (Coleraine), Bristol and Edinburgh (Queen Margaret University College)) and involved the participation of 300 overweight and obese males and females aged 21-60 years in a community setting. RESULTS: Significant weight loss was achieved by all dieting groups (5-9 kg at 6 months) but no significant difference was observed between diets at 6 months. The Weight Watchers and Rosemary Conley (low-fat) diets were followed by significant reductions in plasma LDL cholesterol (both -12.2 % after 6 months, P < 0.01), whereas the Atkins (low-carbohydrate) and Weight Watchers diets were followed by marked reductions in plasma TAG (-38.2 % and -22.6 % at 6 months respectively, P < 0.01). These latter two diets were associated with an increase in LDL particle size, a change that has been linked to reduced CVD risk. CONCLUSIONS: Overall, these results demonstrate the favourable effects of weight loss on lipid-mediated CVD risk factors that can be achieved through commercially available weight-loss programmes. No detrimental effects on lipid-based CVD risk factors were observed in participants consuming a low-carbohydrate diet.

Ultrastructural observation of electron irradiation damage of lamellar bone.

The ultrastructure of murine femoral lamellar bone and the effect of electron irradiation (200 kV) on collagen and mineral features were investigated using in situ high resolution transmission electron microscopy (HRTEM). Bands of collagen fibrils were mostly aligned parallel to the long axis of the bones, with some bands of fibrils inclined in longitudinal sections. The similarity of the ultrastructure between the longitudinal and transverse sections supports the rotated plywood structure of the lamellar bone. The collagen fibrils appeared damaged and the mineral crystals were coarsened after electron irradiation. Continuous diffraction rings became spotty and the contrast between rings and the background became sharper, further suggesting coarsening of apatite crystals and increased crystallinity after irradiation. No new phases were observed after irradiation. Both the damage to collagen and coarsening of apatite crystals can deteriorate the strength and integrity of bone, and may provide insight into fracture in patients who have undergone radiation therapy.

Serial measurement of uterine blood flow from mid to late gestation in growth restricted pregnancies induced by overnourishing adolescent sheep dams.

Uterine blood flow (UtBF) is a major regulator of transplacental fetal nutrient supply. The aim was to serially measure uterine blood flow from mid to late pregnancy in a paradigm of relatively late onset placental and fetal growth restriction. Singleton bearing adolescent dams was fed high (H) or control (C) nutrient intakes to induce putatively compromised or normal pregnancies, respectively. A perivascular flow probe was attached to the uterine artery of the gravid horn on Day 83 of gestation and UtBF was then recorded continuously for 2h, three times weekly until approximately Day 135, when pregnancies were either terminated or ewes allowed to deliver at term (approximately Day 145). Pregnancy outcome was determined at term in contemporaneous ewes without UtBF assessment. Placental and fetal weights were lower (P<0.001) in H compared with C intake groups and were independent of flow probe surgery and monitoring. Uterine blood flow was lower in H compared with C groups at the first assessment (Day 88, P<0.001) and was positively correlated with adjusted fetal weight at term, irrespective of treatment group (P<0.01). UtBF increased throughout the second half of gestation in both groups. Linear regression analysis of UtBF against day of gestation revealed that the slope was equivalent (5.5 vs. 5.3ml/min per day) and the mean intercept lower (212 vs. 370ml/min, P<0.001) in H compared with C groups, respectively. This study demonstrates the feasibility of serially measuring UtBF within the same individual sheep for a protracted period during the second half of gestation. UtBF was already lower at mid gestation in putatively growth restricted compared with control pregnancies, ahead of any reduction in placental and fetal weight, but increased similarly during the second half of gestation in both groups. These data are commensurate with the reported decrease in placental angiogenic growth factor expression at mid gestation, and, indicate that attenuated UtBF is an early defect in this adolescent paradigm.

Habitual fish consumption does not prevent a decrease in LCPUFA status in pregnant women (the Seychelles Child Development Nutrition Study).

Information on the status of long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy and breast milk in very high fish-eating populations is limited. The aim of this study was to examine dietary intake and changes in fatty acid status in a population of pregnant women in the Republic of Seychelles. Serum docosahexaenoic acid (DHA) decreased significantly between 28-week gestation and delivery (n=196). DHA status did not correlate significantly with length of gestation and was not associated with self-reported fish intake, which was high at 527 g/week. In breast milk, the ratio of DHA to arachidonic acid (AA) was consistent with those observed in other high fish-eating populations. Overall the data suggest that high exposure to LCPUFAs from habitual fish consumption does not prevent the documented decrease in LCPUFA status in pregnancy that occurs as a result of foetal accretion in the third trimester of pregnancy.

Animal Research Pathology: Regulatory and Safety Considerations.

Animal research pathology encompasses a wide array of procedures and may involve work with a variety of animal species and hazards. To protect laboratory personnel and ensure data integrity, pathologists must be familiar with the activities performed in their laboratories and the applicable regulatory and safety requirements. Failure to address issues proactively may result in exposure of personnel to hazardous materials and/or collection of data in a manner that does not conform to animal welfare or quality control standards. This manuscript provides a brief introduction to important animal research pathology regulatory and safety considerations. The importance of close communication between the principal investigator, pathologist, laboratory personnel, Institutional Animal Care and Use Committee, and institutional safety office/experts is emphasized and a mechanism for improving communication is discussed.

The effect of nicotine in vitro on the integrity of tight junctions in Caco-2 cell monolayers.

Ulcerative colitis is characterised by impairment of the epithelial barrier and tight junction alterations resulting in increased intestinal permeability. UC is less common in smokers with smoking reported to decrease paracellular permeability. The aim of this study was thus to determine the effect of nicotine, the major constituent in cigarettes and its metabolites on the integrity of tight junctions in Caco-2 cell monolayers. The integrity of Caco-2 tight junctions was analysed by measuring the transepithelial electrical resistance (TER) and by tracing the flux of the fluorescent marker fluorescein, after treatment with various concentrations of nicotine or nicotine metabolites over 48 h. TER was significantly higher compared to the control for all concentrations of nicotine 0.01-10 microM at 48 h (p<0.001), and for 0.01 microM (p<0.001) and 0.1 microM and 10 microM nicotine (p < 0.01) at 12 and 24 h. The fluorescein flux results supported those of the TER assay. TER readings for all nicotine metabolites tested were also higher at 24 and 48 h only (p < or = 0.01). Western blot analysis demonstrated that nicotine up-regulated the expression of the tight junction proteins occludin and claudin-1 (p < or = 0.01). Overall, it appears that nicotine and its metabolites, at concentrations corresponding to those reported in the blood of smokers, can significantly improve tight junction integrity, and thus, decrease epithelial gut permeability. We have shown that in vitro, nicotine appears more potent than its metabolites in decreasing epithelial gut permeability. We speculate that this enhanced gut barrier may be the result of increased expression of claudin-1 and occludin proteins, which are associated with the formation of tight junctions. These findings may help explain the mechanism of action of nicotine treatment and indeed smoking in reducing epithelial gut permeability.

Nutritional modulation of adolescent pregnancy outcome -- a review.

The risks of miscarriage, prematurity and low birth weight are particularly acute in adolescent girls who are still growing at the time of conception. The role of maternal nutrition in mediating pregnancy outcome in this vulnerable group has been examined in sheep models. When singleton bearing adolescent dams are overnourished to promote rapid maternal growth throughout pregnancy, growth of both the placenta and fetus is impaired, and birth occurs prematurely relative to control adolescents of equivalent age. Studies at mid-gestation, prior to alterations in placental mass, suggest that reduced proliferation of the fetal trophectoderm, impaired angiogenesis, and attenuated uteroplacental blood flows are early defects in placental development. By late pregnancy, relative placental mass is reduced by 45% but uteroplacental metabolism and placental glucose transfer capacity remain normal when expressed on a placental weight specific basis. The asymmetrically growth-restricted fetuses are hypoxic, hypoglycemic and have reduced insulin and IGF-1 concentrations. Absolute umbilical nutrient uptakes are attenuated but fetal utilisation of glucose, oxygen and amino acids remains normal on a fetal weight basis. This suggests altered sensitivities to metabolic signals and may have implications for subsequent metabolic health. At the other end of the nutritional spectrum, many girls who become pregnant have inadequate or marginal nutritional status during pregnancy. This situation is replicated in a second model whereby dams are prevented from growing during pregnancy by relatively underfeeding. Limiting maternal intake in this way gradually depletes maternal body reserves leading to a lower transplacental glucose gradient and a modest slowing of fetal growth in late pregnancy. These changes appear to be independent of alterations in placental growth per se. Thus, while the underlying mechanisms differ, maternal intake at both ends of the nutritional spectrum is a powerful determinant of fetal growth in pregnant adolescents.

Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults.

OBJECTIVE: To assess the vitamin D status of healthy young people living in Northern Ireland and the effect of vitamin D supplementation on vitamin D status and bone turnover. DESIGN: Double-blinded randomised controlled intervention study. SETTING: University of Ulster, Coleraine, Northern Ireland. SUBJECTS: In total, 30 apparently healthy students (15 male and 15 female subjects), aged 18-27 years, were recruited from the university, with 27 completing the intervention. INTERVENTIONS: Subjects were randomly assigned, to receive either 15 microg (600 IU) vitamin D(3) and 1,500 mg calcium/day (vitamin D group), or 1,500 mg calcium/day (control group) for 8 weeks between January and March. Vitamin D status, bone turnover markers, serum calcium and parathyroid hormone concentrations were measured at baseline and post intervention. RESULTS: At baseline, vitamin D status was low in both the vitamin D group (47.9 (s.d. 16.0)) and the control group (55.5 (s.d. 18.6) nmol/l 25(OH)D). Post intervention vitamin D status was significantly higher in the vitamin D-treated group (86.5 (s.d. 24.5)) compared to the control group (48.3 (s.d. 16.8) nmol/l) (P<0.0001). There was no significant effect of supplementation on bone turnover markers or PTH concentrations. CONCLUSIONS: This study suggests that young adults in Northern Ireland do not consume an adequate daily dietary intake of vitamin D to maintain plasma vitamin D concentrations in the wintertime. A daily supplement of 15 microg vitamin D(3) significantly increased vitamin D status in these individuals to levels of sufficiency. Achievement of an optimum vitamin D status among young adults may have future positive health implications.

Investigation of the medium-term effects of Olibratrade mark fat emulsion on food intake in non-obese subjects.

OBJECTIVE: To investigate the effect of Olibra fat emulsion on medium-term food intake and appetite in non-obese subjects. DESIGN: Double-blind, placebo-controlled, within-subject crossover. SETTING: University of Ulster, Coleraine. SUBJECTS: A total of 28 subjects (14 male, 14 female). INTERVENTIONS: Subjects were randomly assigned to receive either a 200 g portion of test (5 g of Olibra fat) or control (5 g milk fat) yoghurt for breakfast for 2 x 3 week 'study' phases, separated by a 3-week 'wash-out' phase. On days 1, 8 and 22 of the study phases, food intake 4 h post-consumption of the yoghurt was assessed by pre- and post-covert weighing at an ad libitum buffet-style test lunch. Throughout each of these study days, appetite was assessed using visual analogue scales (VAS) at regular intervals. For the remainder of the study days, and the following 24 h ('post-study days'), subjects reported their food intake using weighed dietary records. RESULTS: Consumption of the Olibra emulsion had no significant effect on mean energy, macronutrient or amounts of food consumed at the lunch 4 h post-consumption. Self-reported food intakes indicated that there was no significant effect of the emulsion on energy intakes for the remainder of each study day and post-study days. There was considerable individual variation in food intakes following consumption of the Olibra emulsion, with 46, 59 and 57% of subjects reducing their energy intakes at lunch on days 1, 8 and 22. There was no consistent effect of the emulsion on appetite ratings. CONCLUSIONS: In contrast to earlier studies, there was no evidence of a short- or medium-term effect of the Olibra emulsion on food intake or appetite. This could be owing to numerous confounding factors influencing eating behaviour and/or the different study design used in the present study.

The effects of acute nutrient restriction in the mid-gestational ewe on maternal and fetal nutrient status, the expression of placental growth factors and fetal growth.

This study explores the hypothesis that acute under-nutrition in mid-gestation reduces maternal and fetal nutrient status and affects the expression of specific regulators of placental growth and function. Welsh Mountain ewes were fed a concentrate diet plus wheat straw to provide 100% of their maintenance requirements. The concentrate ration of nutrient restricted (NR) ewes was reduced from day (d) 83 of gestation and withdrawn from d85 to d90. At d90, half the ewes (NR m = 7, control n = 8) were euthanased. The remainder (NR n = 9, control n = 9) were fed their maintenance diet until slaughter at d135. Maternal plasma insulin and IGF-I concentrations decreased during nutrient restriction and NEFA concentrations increased. Fetal IGF-I and insulin concentrations were unaltered by maternal diet. Placental VEGF mRNA expression was reduced at d90 (P < 0.05). IGFBP-3 and IGFBP-2 mRNA expression was reduced at d90 (P < 0.05) and d135 (P < 0.05), respectively. Placental weight was significantly lower in NR ewes at d90 (P < 0.05) and the distribution of placentomes shifted towards the everted phenotype at d135 (P < 0.05). Reduced thoracic girth and uterine fluid volume at d90 (P < 0.05) and decreased fetal lung weight at d90 (P < 0.05) and d135 (P < 0.05) suggest spatial limitation of lung expansion. In summary, acute NR in mid-gestation reduced anabolic drive and mobilised lipid stores in the maternal compartment, whilst fetal nutrient status was maintained. This was accompanied by changes in placental VEGF and IGFBP expression. The growth of the fetal lung appears to have been compromised and this may have adverse consequences for subsequent neonatal respiratory function.

Animal models of placental angiogenesis.

The study of the development of the fetal membranes is an ancient one, and the importance of placental vascular development to placental function has long been recognized. Animal models have been important in these studies, as they allow for controlled experiments and analysis of multiple time-points during pregnancy. Since the demonstration nearly 20 years ago that the placenta produces angiogenic factors, the major factors regulating placental angiogenesis have been identified. These major factors include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), the angiopoietins (ANG), and their receptors. Recently, sophisticated computerized image analysis methods have been developed to establish the pattern of placental vascular development in sheep. The maternal placental capillary bed develops primarily by increased size of capillaries, with only small increases in capillary number or surface densities. In contrast, the microvasculature of the fetal placenta develops primarily by increased branching, resulting in a large increase in capillary number and surface densities. These observations help to explain the relatively large increase in umbilical blood flow and nutrient delivery to the fetus that occurs during the last half of gestation. In addition, expression of mRNAs for VEGF, bFGF, ANG, and their receptors have recently been correlated with normal placental vascular development in sheep, and further refinement of these mathematical models is warranted. Lastly, the recent development of animal models of compromised pregnancies, including those resulting from maternal nutrition (both restriction and excess), multiple fetuses, environmental stress (heat stress and high altitude), and fetal and maternal breed effects, has already indicated that reductions in placental vascular development and expression of angiogenic factors are probably a root cause of fetal growth restriction. With these methods and models now in place, we should soon be able to establish the mechanisms involved in both normal and abnormal placental angiogenesis.