Insulin-like growth factor-I (IGF-I) is a growth hormone that acts as a key modulator of the growth axis. Serum and plasma concentrations of IGF-I have been linked to economically important traits in beef cattle. In order to determine whether concentrations of IGF-I differed among breeds of beef cattle, plasma samples from purebred and crossbred animals were analyzed. Two calf crops were derived from three-breed diallel matings using temperate and tropically-adapted breeds of cattle. The breeds consisted of temperate Bos taurus (A; Angus), tropical Bos indicus (B; Brahman), and tropical Bos taurus (R; Romosinuano). Plasma samples were obtained from 10 heifers and 10 steers of each breed-type at weaning, and two dates post-weaning. Concentrations of IGF-I were determined by radioimmunoassay (RIA). Breed differences were observed (P < 0.001). Relative to the temperate Bos taurus breed, IGF-I was greater in tropically-adapted breed-types. In an effort to select for the improvement of economically important traits, experiments were performed to explore the possible use of concentration of IGF-I and temperament assessment as tools for selection. Using a Calan gate system, 3 Brahman heifer crops were fed during70-day trials. Performance and feed intake data were collected to determine feed efficiency. Temperament, determined by exit velocity and pen score, was evaluated at weaning. Serum samples were taken at weaning and days 0 and 70 of each trial. Concentrations of IGF-I and cortisol were determined by RIA. Correlations including IGF-I were weak (P > 0.05). Temperament had no significant effect on RFI but may affect ADG. In an attempt to examine the relationship between IGF-I and RFI, body weight and feed intake data were collected during individual finishing phase feeding trials, on steers at El Reno, OK. The breeds consisted of temperate Bos taurus (A; Angus), tropical Bos indicus (B; Brahman), and tropical Bos taurus (R; Romosinuano). Plasma samples were obtained from 10 steers of each breed-type at weaning and days 0 and 60 of each finishing phase. Concentrations of IGF-I were determined by RIA. Correlations between IGF-I and RFI were weak (P > 0.05). Breed and year significantly influenced RFI (P < 0.01).

Insulin-like growth factor-I (IGF-I) is a mitogenic polypeptide that induces proliferation and activation of kinase pathways in MCF-7 breast cancer cells. The role of estrogen receptor α (ERα) in mediating responses induced by IGF-I was investigated in cells transfected with small inhibitory RNA for ERα (iERα) or cotreated with the pure antiestrogen ICI 182780. The results showed that IGF-I-dependent phosphorylation of Akt and MAPK, induction of G1–S-phase progression and enhanced expression of cyclin D1 and cyclin E were dependent on ERα. Moreover, these IGF-I-induced responses were also inhibited by the antiestrogen ICI 182780, suggesting that the effects of ICI 182780 as an inhibitor of IGF-I induced responses in breast cancer cells are primarily related to downregulation of ERα. Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon receptor (AhR). We investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin, in MCF-7 breast cancer cells, HepG2 human liver cells and mouse Hepa-1 cells. The dietary phytochemicals exhibited substantial cell context–dependent AhR agonist as well as antagonist activities, and these are factors that must be considered in risk assessment of overall exposures to AhR agonists. Halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8- pentachlorodibenzo-p-dioxin (PeCDD), 3,3’,4,4’,5-pentachlorobiphenyl (PCBP), 2,3,7,8- tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) bind and activate the aryl hydrocarbon receptor (AhR). It has been assumed that these compounds only differ in their potencies. The SAhRM-like activity of the 5 HAHs was investigated by determining ligand structure dependent differences in their induction of CYP1A1 and interactions of the AhR with a series of coactivators in a mammalian two-hybrid assay in three AhR-responsive cell lines, including mouse Hepa-1, Human HEK293 and human Panc1 cells. There were multiple structure-dependent differences in activation of luciferase activity in these cell lines transfected with VP-AhR and six different GAL4-coactivator chimeras and a GAL4-response element-luciferase promoter construct. The results show that HAHs selectively interact with coactivators and these interactions are dependent on cell-context, and even among HAHs, these compounds exhibit selective receptor modulator activity.

Objectif Ce travail se veut une contribution à l’amélioration de la santé des enfants du Burkina Faso et de l’Afrique en général. Il vise à l’identification de meilleures stratégies de diagnostic et de pronostic des enfants atteints de malnutrition. Méthodes · Dans une première étape, nous avons validé une méthode permettant la quantification de l’IGF-I à partir de sang prélevé sur papier buvard chez des enfants de moins de cinq ans, dont les valeurs d’IGF-I sont très basses. Une collecte des échantillons de sang sur tube (sérum), sur papier buvard à la température de 4 °C et sur papier buvard à la température ambiante (30-35 °C) a été réalisée auprès de 13 enfants burkinabè âgés de 0 à 59 mois qui ont consulté au service de Pédiatrie du CHU Yalgado Ouedraogo de Ouagadougou et au Centre Médical de Kossodo à Ouagadougou. Les mesures de l’IGF-I ont été effectuées sur IGF-I RIA, après séparation des protéines porteuses en utilisant la chromatographie sur Sep-Pack. · Nous avons ensuite réalisé une étude transversale en population auprès générale auprès de 400 enfants en bonne santé apparente à Ouagadougou (Burkina Faso). La collecte de sang s’est faite sur papier buvard. · Enfin, nous avons mené une étude de cohorte auprès des enfants admis dans 2 centres de réhabilitation et d’éducation nutritionnelle à Ouahigouya dans le Nord du Burkina Faso. Les enfants ont été suivis de l’admission à leur sortie et les données anthropométriques ainsi que des échantillons de sang sur papier buvard ont été collectés à l’admission, au 7ème Jour et au 14ème Jour. Résultats · L’étude de validation a montré qu’il existe une excellente corrélation entre les taux sériques d’IGF-I et les taux d’IGF-I sur papier buvard conservés à 4 °C ou à la température ambiante d’une zone tropicale (30 – 35 °C). · L’étude transversale en population a permis d’obtenir les valeurs de référence de l’IGF-I chez les enfants de moins de 5 ans au Burkina Faso. Les concentrations moyennes d’IGF-I sont plus élevées chez les filles que chez les garçons. De la naissance à 24 mois, l’IGF-I décroît et après 24 mois, il y a une augmentation de l’IGF-I chez les filles comme chez les garçons. · Les résultats de l’étude de cohorte en milieu hospitalier ont montré des valeurs de l’IGF-I très basses à l’admission. Ensuite, nous avons observé une augmentation des valeurs d’IGF-I au 7ème jour et cette augmentation a continué jusqu’au 14ème jour. Une corrélation significative a été observée entre le gain pondéral et le gain d’IGF-I au 7ème jour et au 14ème jour. Conclusion Les études que nous avons réalisées démontrent qu’il est possible d’utiliser le papier buvard pour la collecte des échantillons de sang dans le cadre des études épidémiologiques dans les pays où les contraintes matérielles ne permettent pas toujours de maintenir une chaîne de froid efficace pour la conservation des échantillons sanguins et chez de très jeunes enfants chez lesquels il est très malaisé d’obtenir des échantillons de sang par ponction veineuse. Les valeurs de référence de l’IGF-I établies peuvent être utiles pour le diagnostic et la surveillance nutritionnels ainsi que pour les évaluations des pathologies endocriniennes chez les enfants de moins de 5 ans dans le contexte d’un pays tropical comme le Burkina Faso. Mais des études complémentaires pourraient mettre en évidence la valeur pronostic d’une récupération faible ou importante de l’IGF-I après un épisode de malnutrition sévère. Il est plausible que la perte plus ou moins importante d’un potentiel de croissance lors d’une période de malnutrition sévère soit un indicateur de mauvais développement à l’adolescence ou à l’âge adulte.

Insulin-like growth factor-I (IGF-I) is a mitogenic polypeptide that induces proliferation and activation of kinase pathways in MCF-7 breast cancer cells. The role of estrogen receptor α (ERα) in mediating responses induced by IGF-I was investigated in cells transfected with small inhibitory RNA for ERα (iERα) or cotreated with the pure antiestrogen ICI 182780. The results showed that IGF-I-dependent phosphorylation of Akt and MAPK, induction of G1–S-phase progression and enhanced expression of cyclin D1 and cyclin E were dependent on ERα. Moreover, these IGF-I-induced responses were also inhibited by the antiestrogen ICI 182780, suggesting that the effects of ICI 182780 as an inhibitor of IGF-I induced responses in breast cancer cells are primarily related to downregulation of ERα. Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon receptor (AhR). We investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin, in MCF-7 breast cancer cells, HepG2 human liver cells and mouse Hepa-1 cells. The dietary phytochemicals exhibited substantial cell context–dependent AhR agonist as well as antagonist activities, and these are factors that must be considered in risk assessment of overall exposures to AhR agonists. Halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8- pentachlorodibenzo-p-dioxin (PeCDD), 3,3’,4,4’,5-pentachlorobiphenyl (PCBP), 2,3,7,8- tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) bind and activate the aryl hydrocarbon receptor (AhR). It has been assumed that these compounds only differ in their potencies. The SAhRM-like activity of the 5 HAHs was investigated by determining ligand structure dependent differences in their induction of CYP1A1 and interactions of the AhR with a series of coactivators in a mammalian two-hybrid assay in three AhR-responsive cell lines, including mouse Hepa-1, Human HEK293 and human Panc1 cells. There were multiple structure-dependent differences in activation of luciferase activity in these cell lines transfected with VP-AhR and six different GAL4-coactivator chimeras and a GAL4-response element-luciferase promoter construct. The results show that HAHs selectively interact with coactivators and these interactions are dependent on cell-context, and even among HAHs, these compounds exhibit selective receptor modulator activity.

Cows in first (n = 163) and second (n = 101) lactation were studied to determine if reproduction, progesterone (P4), IGF-I, insulin, NEFA, and milk production differed between genetic groups. Thirty-five cows were Holstein-Jersey (HJ) crosses, 48 were Jersey-Holstein (JH) crosses, 51 were Holsteins (HH), and 29 were Jerseys (JJ). Days open (DO) was affected by genetic group. HH had 168.6 ± 9.6 DO which was different from HJ (142.9 ± 11.3 d), JJ (132.1 ± 12.1 d), and JH (127.2 ± 9.3 d). HH had 2.4 ± 0.1 services per conception which was different from JH (1.9 ± 0.1), but not different from HJ (2.1 ± 0.2) or JJ (2.1 ± 0.2). In HH P4 concentrations (1.6 ± 0.11 ng/mL) were not different from HJ (1.5 ± 0.12 ng/mL), but lower than JH (1.8 ± 0.10 ng/mL) and JJ (1.8 ± 0.13 ng/mL). NEFA concentrations were greater in lactation 2 (0.52 ± 0.02 mEq/L) than in lactation 1 (0.45 ± 0.02 mEq/L). Insulin in HH (0.83 ± 0.03 ng/mL) was not different from HJ (0.87 ± 0.04 ng/mL) or JH (0.76 ± 0.03 ng/mL), but was greater than JJ (0.66 ± 0.04 ng/mL). IGF-I gradually increased over the 10 wk period. The HH produced 10,348 ± 208 kg of milk, which was greater than the HJ (9,129 ± 230 kg), the JH (9,384 ± 192 kg), and the JJ (7,080.9 ± 261 kg). Reproductive measures, milk yield, hormones and metabolites were affected by genetic groups. / Master of Science

No description available.

Increased circulating levels of glucocorticoids observed in many catabolic conditions play a major role in the induction of muscle atrophy. Indeed, inhibition of glucocorticoid action by glucocorticoid receptor antagonist attenuates and, in some cases, abolishes muscle atrophy. Circulating and tissue levels of IGF-I, a growth factor that stimulates the development of muscle mass, are frequently reduced in response to glucocorticoids. This decline could therefore trigger muscle atrophy in catabolic conditions. Indeed, systemic administration of IGF-I prevents glucocorticoid-induced muscle atrophy. However, use of systemic IGF-I administration is limited by its hypoglycemic and cardiac hypertrophic actions. Moreover, local IGF-I seems to play a more important role in the regulation of muscle mass than systemic IGF-I. Therefore, to limit loss of muscle mass observed in catabolic states, IGF-I administration must mimic as close as possible the autocrine production of IGF-I. The aim of this thesis was to investigate whether the restoration of IGF-I muscle content could reverse muscle atrophy induced by glucocorticoids. In this work we have tested the hypothesis that the local decrease in muscle IGF-I content might be responsible for the muscular atrophy induced by glucocorticoids. In our work, we have demonstrated that localized overexpression of IGF-I by gene electrotransfer prevents muscle atrophy in glucocorticoid-treated rats. High rate of fiber transfection and long term gene expression were obtained by combining multiple injection sites of DNA with electroporation. Human IGF-I gene electrotransfer using this optimised protocol resulted in increased muscle IGF-I mRNA and protein levels together with prevention of loss of skeletal muscle mass. Furthermore, alterations in the Akt/GSK-3â/â-catenin signaling pathway caused by glucocorticoids were prevented by local IGF-I gene overexpression. Finally, muscle overexpression of caAkt, dnGSK-3b and ÄNb-catenin was sufficient to mimic the anti-atrophic effect of IGF-I supporting the role of this signalling pathway in muscle atrophy caused by glucocorticoids. Taken together, our results show, for the first time in vivo, the role of the IGF-I/Akt/GSK-3b/b-catenin pathway in the skeletal muscle atrophy caused by glucocorticoids. In conclusion, our work highlights the crucial role of decreased muscle IGF-I in glucocorticoid-induced muscle atrophy. Indeed, the data presented in this thesis support the fact that the atrophic action of glucocorticoids is in part due to the downregulation of IGF-I, leading to the inhibition of its signalling pathways while restoration of muscle IGF-I levels is able to counteract totally muscle atrophy.

Skeletal muscle regeneration involves a tightly regulated coordination of cellular and signaling events to remodel and repair the site of injury. When this coordination is perturbed, the regenerative process is impaired. The expression of insulin-like growth factor-I (IGF-I) is robust in the typical muscle regenerative program, promoting cell survival and increasing myoblast activity. In this project, we found that severely depressed IGF-I expression and intracellular signaling in aged skeletal muscle coincided with impaired regeneration from ischemia/reperfusion (I/R). To hasten muscle regeneration, we developed the PEGylated fibrin gel (PEG-Fib) system as a means to intramuscularly deliver IGF-I in a controlled manner to injured muscle. This strategy resulted in greatly improved muscle function and histological assessment following 14 days of reperfusion, which are likely mediated by improved myofiber survival. Recent evidence suggests macrophages (MPs) are responsible for the upregulation of IGF-I following injury, therefore we developed a rapid, reproducible, and cost-effective model of investigating MP profiles in injured muscle via flow cytometry. Using information gathered from this model, we found that increasing the number of a non-inflammatory MP population improves the recovery of muscle from I/R. These data demonstrate that immunomodulatory therapies have the potential to greatly improve the recovery of skeletal muscle from injury. / text

Submitted by Tatiana Silva (tsilva@icict.fiocruz.br) on 2012-12-27T17:57:17Z No. of bitstreams: 1 luciana_s_rodrigues_ioc_bcm_0026_2010.pdf: 8319063 bytes, checksum: 23ce271789168f4d9723b9a7df6ffe11 (MD5) / Made available in DSpace on 2012-12-27T17:57:17Z (GMT). No. of bitstreams: 1 luciana_s_rodrigues_ioc_bcm_0026_2010.pdf: 8319063 bytes, checksum: 23ce271789168f4d9723b9a7df6ffe11 (MD5) Previous issue date: 2010 / Fundação Oswaldo Cruz.Instituto Oswaldo Cruz. Rio de janeiro, RJ, Brasil / A lesão neural é uma das principais consequências da hanseníase e responsável pela instal ação de deformidades e incapacidades físicas, al ém de contribuir para o esti gma da doença. O dano ao nervo é exacerbado com o desenvolvimento de episódi os reaci onais (Ti po I e Ti po II) e está correlaci onado à resposta imunol ógi ca desenvolvida pel o indivíduo, contra o Mycobacterium leprae – agente eti ol ógico da hanseníase que apresenta especi al tropismo por macrófagos e células de Schwann (CS) nos nervos periféri cos. Os fatores de crescimento semelhante à Insulina (IGFs) são hormôni os pept ídi cos implicados no metabolismo, indução de proliferação, inibição de apoptose e diferenciação de diferentes ti pos cel ulares. Evi dências da li teratura apontam também propri edades imunomoduladoras e anti -inflamatóri as do IGF-I. O objetivo do presente estudo vi sa a invest i gação da parti cipação do si stema IGF na infecção pel o M. leprae. Ini cialmente, verificamos o efei to anti -apoptóti co da bactéri a sobre CS humanas primárias e da linhagem ST88-14 cul t ivadas em condições livres de soro pel a inibição da at ivação de caspase-3. Demonstramos, ainda, através de ensai os de imunoci toquímica, que o bacil o é capaz de induzir a proliferação da CS, tal efei to provavelmente mediado pel a indução de IGF-I, confi rmado pel a técnica de RT-PCR quant i tativo e pel a detecção da proteína em sobrenadantes de cul tura através de ensai o imunoenzimát i co. Na segunda etapa do trabalho, avaliamos a part i cipação do IGF-I ci rculante na evol ução natural da hanseníase. Utilizando ELISA quimi oluminescente, quantificamos os níveis de IGF-I, da principal proteína ligadora de IGF (IGFBP-3) e TNF-a no soro de indivíduos sadi os e pacientes que desenvolveram ou não quadros reacionais ao l ongo do tratamento. No caso dos pacientes reaci onais, a dosagem de IGF-I, IGFBP-3 e TNF-a fo i realizada em duas etapas: i ) no momento do diagnóstico e ii ) durante o aparecimento da reação, antes do tratamento específico. Ini cialmente, numa comparação entre paci entes que não desenvolveram reação, verificamos que 81% e 72% dos paci entes lepromatosos (LL) apresentaram níveis de IGF-I e IGFBP-3, respectivamente, abaixo do normal por i dade, diferentemente dos paci entes com outras formas clínicas. Dentre os pacientes reaci onais, 93% e 86% do grupo BL também apresentou níveis de IGF-I e IGFBP-3, respectivamente, abaixo do normal por i dade, diferentemente do grupo BL não-reaci onal , que apresentou níveis de IGFs similares aos indivíduos sadi os. Durante o desenvolvimento dos epi sódi os reaci onais, houve uma queda dos níveis de IGF-I, IGFBP-3 e da rel ação IGF/TNF-a no grupo LL com reação ti po II. Já no grupo de paci entes BL, observamos um aumento dos níveis de IGF-I e IGFBP-3, como uma tentativa de alcançar os níveis normais. Nossos dados sugerem a xv parti cipação destes fatores de crescimento endócrinos na ínt ima relação entre bacil o e a CS, como uma estratégi a de obtenção e manutenção de um nicho favorável de mul t iplicação e, ainda, os revelam como potenci ais candidatos a bi omarcadores dos episódi os reaci onais na hanseníase. / Neural injury is a maj or consequence of l eprosy and responsible for the disabili t ies installat i on, beyond to contribute to the st i gma of the disease. The nerve damage is exacerbated by the devel opment or l eprosy react i ons (Type I and Type II) and is correl ated to the immune response against Mycobacterium leprae – et i ol ogi c agent of leprosy that has especial tropism for macrophages and Schwann cells (SC) in peri pheral nerves. Insulin-like growth factors (IGFs) are pept i de hormones involved in metabolism, proliferati on induct i on, apoptosis inhibi t i on and cell different i at i on. Evidence from the li t erature also indicate immunomodulatory and ant i -inflammatory properti es of IGF-I. The aim of this study is to investi gate the involvement of IGF system in the M. leprae infect i on. Ini t ially, we verified the ant i -apoptoti c effect of the bacteria on human primary CS and ST88-14 lineage growing in serum-f ree condi t i ons by inhibi t ing caspase-3 activat i on. It was also demonstrated by immunocytochemistry, that the bacill us is able to induce the SC proliferat i on, this effect i s probably mediated by induct i on of IGF-I, as verified by quant i tative RT-PCR and confirmed by protein detecti on supernatants using immunoenzimat i c assay (ELISA). On the second phase we evaluate the parti cipat i on of ci rculating IGFs in the natural course of leprosy. Through chemi ol uminescent ELISA, we quantified the IGF-I, the main IGF binding protein (IGFBP-3) and TNF-a serum levels in heal t hy individuals and pat i ents who devel oped or not reacti onal states during the treatment. In the case of react i onal pat i ents, the IGF-I, IGFBP-3 and TNF-a was performed in two steps: i ) at the diagnosis of leprosy and ii) during react i onal episode, pri or to specific treatment. Ini t i ally, a comparison of nonreact i onal pat i ents, we found that 81% and 72% of lepromatous l eprosy (LL) showed IGF-I and IGFBP-3 levels, respectively, bel ow normal for age, unlike pat i ents wi th other clinical forms. Among the reacti onal pat i ents, 93% and 86% of BL group also showed IGF-I and IGFBP-3 levels, respectively, bel ow normal for age, unlike the nonreact i onal BL group, wi ch showed similar levels of IGFs to heal thy individuals. During the devel opment of reacti onal episodes, there was a decrease in the levels of IGF-I, IGFBP-3 and the IGF/TNF-a rat i o in the LL group wi t h type II reacti on. In the BL group undergoing type II reacti on, the IGF-I and IGFBP-e levels increased, as an attempt to reach normal levels. Our data suggest the involvement of these growth factors in the relat i onship between bacilli and CS as a strategy for obtaining and maintaining a favorable niche for mul t iplicat i on, and also reveal the IGFs as potencial candidates for bi omarkers of react i onal episodes in leprosy.

During pregnancy, increased uterine blood-flow and efficient placental perfusion is essential for a successful outcome. Despite the essential role of these vascular beds, data on the physiological mechanisms involved in the maintenance of a high-flow/low resistance circulation within the uterus and placenta are limited. The need to fully understand the regulation of blood-flow within the uterine and feto-placental circulations is further highlighted by pathological pregnancies which are characterised by vascular dysfunction within these circulations. Oestrogen and insulin-like growth factor-I (IGF-I) levels increase during pregnancy and correlate with increased uterine blood flow. In vivo and in vitro studies of other vascular beds show that both 17-β oestradiol and IGF-I act as vasodilators. However, surprisingly little is known of their vaso-active effects on human uterine and placental arteries. The aims of the studies described within this thesis, were to investigate, ex vivo, the possible roles of oestrogen and IGF-I in regulating human placental and uterine vascular beds in vivo. Placental chorionic plate arteries and myometrial demonstrated acute vasodilation in response to oestrogen. Vascular bed differences in ER-responsiveness were observed; vasodilation within myometrial arteries was elicited by both oestrogen receptors, ERα and ERβ, although activation of the latter receptor generated a greater response. In contrast, oestrogen-dependent acute vasodilation of placental arteries was via ERβ alone. Furthermore, species differences, between human and rat arteries, were demonstrated in terms of ER-responsiveness. The predominant ER receptor within human arteries studied was ERβ, whilst rat arteries demonstrated a predominantly ERα-mediated mechanism of oestrogen-induced vasodilation. The data presented suggests that within the uterine vascular bed, oestrogen-induced vasodilation involves both an endothelium-dependent and –independent mechanism of action, whilst within the placenta, oestrogen-mediated vasodilation is endothelial-independent. Indeed, data suggests that oestrogen influences the level of intracellular calcium of vascular smooth cells to induce vasodilation of placental arteries.IGF-I did not have a vaso-active effect on chorionic plate arteries isolated from the placenta. However, uterine myometrial arteries exhibited reduced vaso-reactivity in the presence of IGF-I, demonstrated by a depressed response to the vasoconstrictor, U46619. Collectively, these data contribute towards a further understanding of the regulatory mechanisms of the uterine circulation, by identifying oestrogen and IGF-I as possible regulators of the uterine vasculature during pregnancy. Additionally, oestrogen may also have a role in controlling the feto-placental circulation. In the future, targeting ERb may offer a therapeutic strategy for increasing uterine/placental perfusion in pregnancies complicated by vascular dysfunction.