Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

Objectives: Premature birth, defined as less than 37 weeks gestation, affects approximately 12% of all live births around the world. Advances in neonatal care have resulted in the increased survival of infants born prematurely. Although prematurity is a known risk factor for different cardiovascular diseases, little is known about the pathophysiology of vasculature during premature gestation and angiopoietic factors network during premature birth. Aims: The objective of this study was to determine whether the profile of several pro-angiogenic and anti-angiogenic factors in umbilical cord blood (UCB) is different in healthy appropriate-for-gestational-age preterm newborns and normal term babies. The second aim of this study was to investigate the microRNA (miRNAs) expression profile in UCB from preterm labor and to detect miRNAs potentially taking part in control of angogenesis-related processes (Angio-MiRs). Methods: Using an immunobead Luminex assay, we simultaneously measured the concentration of Angiogenin, Angiopoietin-1, FGF-acidic, FGF-basic, PDGF-aa, PlGF, VEGF, VEGF-D, Endostatin, Thrombospondin-2, NGF, BDNF, GDNF, and NT-4 in UCB samples collected from the preterm (n = 27) and term (n = 52) delivery. In addition, the global microRNA expression in peripheral blood mononuclear cells (PBMCs) circulating in such UCB samples was examined in this study using microarray MiRNA technique. Results: The concentrations of five from eight measured pro-angiogenic factors (VEGF, Angiopoietin-1, PDGF-AA, FGF-a, and FGF-b) were significantly lower in UCB from preterm newborns. On the contrary, two angiostatic factors (Endostatin and Thrombospondin-2) were significantly up-regulated in preterm UCB. Among analyzed neurotrophins in preterm newborns, the elevated UCB concentration was found only in the case of GDNF, whereas BDNF was significantly reduced. Moreover, two angiopoietic factors, VEGF-D and PlGF, and two neurotrophins, NT4 and NGF, did not differ in concentration in preterm and term babies. We also discovered that among the significantly down-regulated miRNAs, there were several classical Angio-MiRs (inter alia MiR-125, MiR-126, MiR-145, MiR-150, or MiR155), which are involved in angiogenesis regulation in newborn after preterm delivery. Conclusions: This is the first report of simultaneous measurements of several angiopoietic factors in UCB collected from infants during preterm and term labor. Here, we observed that several pro-angiogenic factors were at lower concentration in UCB collected from preterm newborns than term babies. In contrast, the two measured angiostatic factors, Endostatin and Thrombospondin-2, were significantly higher in UCB from preterm babies. This can suggest that distinct pathophysiological contributions from differentially expressed various angiopoietic factors may determine the clinical outcomes after preterm birth. Especially, our angiogenesis-related molecules analysis indicates that preterm birth of healthy, appropriate-for-gestational-age newborns is an “anti-angiogenic state” that may provide an increased risk for improper development and function of cardiovascular system in the adulthood. This work also contributes to a better understanding of the role of miRNAs potentially involved in angiogenesis control in preterm newborns.

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Preterm birth is associated with immune dysregulation which persists in infants exposed to histologic chorioamnionitis

10.1101/2021.04.29.21256310 ◽

2021 ◽

Author(s):

Gemma Sullivan ◽

Paola Galdi ◽

Nis Borbye-Lorenzen ◽

David Q Stoye ◽

Gillian J Lamb ◽

...

Keyword(s):

Immune Response ◽

Preterm Birth ◽

Cord Blood ◽

Preterm Infants ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Postnatal Life ◽

Immune Profile ◽

Histologic Chorioamnionitis

Abstract Objective. To characterise the umbilical cord blood immune profile in preterm infants compared to term-born controls and the postnatal immune response following exposure to histologic chorioamnionitis (HCA) in preterm infants. Design. Descriptive, observational cohort study. Setting. Edinburgh, UK. Population. 118 preterm infants (mean gestational age 29+0 weeks, range 23+2 to 32+0) and 59 term-born controls. Methods. Placental histopathology was used to identify reaction patterns indicative of HCA, and a customised immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group. Results. The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 5 immune proteins on postnatal day 5 (BDNF, C3, IL-8, MIP-1β and MMP-9) when compared to preterm infants who were not exposed. Conclusion. Preterm birth is associated with a distinct immune profile in umbilical cord blood and infants exposed to HCA experience specific alterations in immune function that persist to day 5 of postnatal life.

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Adipokines in umbilical cord blood from children born large for gestational age

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0502 ◽

2016 ◽

Vol 29 (1) ◽

Cited By ~ 7

Author(s):

Ulrik Lausten-Thomsen ◽

Michael Christiansen ◽

Paula Louise Hedley ◽

Jens-Christian Holm ◽

Kjeld Schmiegelow

Keyword(s):

Childhood Obesity ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Maternal Diabetes ◽

Large For Gestational Age ◽

Intrauterine Environment ◽

Appropriate For Gestational Age ◽

Commercial Kits

AbstractThe etiology of childhood obesity and the associated morbidity is multifactorial. Recently, data suggesting a prenatal programming towards later childhood obesity and metabolic deregulation through the intrauterine environment has emerged. This study explored the concentrations of adipokines and their mutual relationship at birth in children born to non-diabetic mothers.Adiponectin, leptin and sOB-R were measured using ELISA-based commercial kits in umbilical cord blood from 60 neonates (30 born large for gestational age [LGA] and 30 born appropriate for gestational age [AGA]). Children exposed to maternal diabetes, chronic disease and preeclampsia were excluded.The LGA group exhibited significantly elevated concentrations of leptin (p<0.001) and of free leptin index (p<0.001) and decreased sOB-R concentrations (p=0.005) when compared to the AGA group, which persisted in multiple regression analysis after taking the gestational age into account (p=0.048, p<0.001 and p<0.001, respectively). Only a trend towards a difference in adiponectin was demonstrated (p=0.057) regardless of adjustment (p=0.150). However, the leptin/adiponectin ratio was elevated in the LGA group (p=0.008), regardless of adjustment (p=0.039).The data indicate a disturbance of adipokines in macrosomic newborns and that the mutual ratios between adipokines may provide a more sensitive marker of metabolic disturbance than any isolated adipokine.

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The Role of Umbilical Cord Blood Concentration of IGF-I, IGF-II, Leptin, Adiponectin, Ghrelin, Resistin, and Visfatin in Fetal Growth

American Journal of Perinatology ◽

10.1055/s-0038-1672141 ◽

2018 ◽

Vol 36 (06) ◽

pp. 600-608 ◽

Cited By ~ 6

Author(s):

Emine Yalinbas ◽

Cigdem Binay ◽

Enver Simsek ◽

Mehmet Aksit

Keyword(s):

Cord Blood ◽

Umbilical Cord ◽

Fetal Growth ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Strong Association ◽

Large For Gestational Age ◽

Term Infants ◽

Igf I ◽

Appropriate For Gestational Age

Objective Herein, we measured the concentration of insulinlike growth factor I (IGF-I), IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin in the umbilical cord blood of newborns categorized as “small for gestational age” (SGA), “appropriate for gestational age” (AGA), and “large for gestational age” (LGA). Our aim was to elucidate the link between the levels of these proteins and fetal growth. Study Design A total of 96 term infants were included and categorized into three weight categories. Their venous cord blood samples were collected to measure the levels of IGF-I, IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin. Results IGF-I, visfatin, and leptin levels showed significant differences among the groups. Pairwise comparisons showed that adiponectin (p = 0.023), resistin (p = 0.025), and ghrelin (p = 0.005) levels were significantly lower in the SGA group than in the LGA group. Correlation analyses showed a strong association of IGF-1, IGF-II, and leptin levels with birth weight (r = 0.644, p < 0.001; r = 0.441, p < 0.001; and r = 0.404, p < 0.001, respectively). Conclusion SGA newborns showed a significantly higher visfatin concentration and lower ghrelin, leptin, resistin, and adiponectin levels than the AGA and LGA newborns did.

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Insulin and glucagon levels of umbilical cord blood in appropriate for gestational age - preterm infants with or without postnatal hypoglycemia

Annals of Pediatric Endocrinology & Metabolism ◽

10.6065/apem.2016.21.2.86 ◽

2016 ◽

Vol 21 (2) ◽

pp. 86 ◽

Cited By ~ 1

Author(s):

Jae Hyun Park ◽

Jin Gon Bae ◽

Shin Kim ◽

Chun Soo Kim ◽

Sang Lak Lee ◽

...

Keyword(s):

Cord Blood ◽

Preterm Infants ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Appropriate For Gestational Age

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Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.722489 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gemma Sullivan ◽

Paola Galdi ◽

Nis Borbye-Lorenzen ◽

David Q. Stoye ◽

Gillian J. Lamb ◽

...

Keyword(s):

Immune Response ◽

Preterm Birth ◽

Cord Blood ◽

Preterm Infants ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Immune Profile ◽

Increased Risk ◽

Histologic Chorioamnionitis

IntroductionPreterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.PopulationFor objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.MethodsPlacental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.ResultsThe umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.ConclusionPreterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

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