Abstract 17312: Hand1 Impairs Angiogenesis in Heart and Placenta

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Jennifer A Courtney ◽  
Helen N Jones
Keyword(s):  
Histological Analysis ◽  
Heart Defects ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Septal Defects ◽  
And Function ◽  
Left Heart Syndrome

Introduction: Congenital heart defects affect approximately 1% of live births, often requiring complex surgeries at birth. The most significant risk factor for surgery survival is birthweight. Proper placental development and function is vital for normal fetal growth. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas. Hand1 has roles in heart and placental development and has been implicated in multiple types of CHD including double right outlet, hypoplastic left heart syndrome, and septal defects. We utilized the Hand1 A126fs/+ mouse to investigate the role of Hand1 in placentation and vascularization. Methods: Hand1 A126fs/+ female mice were time-mated with Nkx2.5cre or Cdh5cre males. Feto-placental units were harvested at E10.5 and E12.5 for histological analysis, vascular assessment by IHC for CD-31, and RNA expression by qPCR. Results: Nkx2.5cre/Hand1 a126fs/+ fetuses demonstrated embryonic lethality by E10.5 due to lack of placental labyrinth formation and vascularization (Figure 1). In contrast, ablation of Hand1 in vascular endothelium (Cdh5cre) did not disrupt placental labyrinth or heart at E12.5. Expression of VegFb, Ang1, Ang2, Flt1, Flk was reduced in Hand1 A126fs/+ ; Nkx2.5cre placentas compared to control littermates, but VegFa expression was increased. Conclusion: Our data demonstrate that Hand1 expression in placental trophoblast, but not endothelium, is necessary for vascularization of the labyrinth and may disrupt multiple angiogenic factors known to be expressed in trophoblast. Alterations in Hand1 may represent a mechanism for abnormal placentation in cases of CHD. Figure 1. H/E (A-C) and CD31 (D-F) images of Hand1 +/+ (A, D), Hand1 A126fs/+ ; Nkx2.5cre (B, E), and Hand1 A126fs/+ ; Cdh5cre (C, F) placentas at day E12.5. Hand1A 126fs/+ ; Nkx2.5cre placentas fail to form labyrinth and fetal vasculature, while Hand1 A126fs/+ ; Cdh5cre placentas develop normally at this timepoint.

scholarly journals Impaired labyrinth formation prevents the establishment of the maternal-fetal interface in conditional Hand1-deficient mice

2020 ◽  
Author(s):  
Jennifer A. Courtney ◽  
James Cnota ◽  
Helen Jones
Keyword(s):  
Heart Development ◽  
Histological Analysis ◽  
Heart Defects ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Septal Defects ◽  
And Function ◽  
Left Heart Syndrome ◽  
Deficient Mice ◽  
Fetal Vessels

AbstractIntroductionCongenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. Placental development and function is vital to ensure normal fetal development. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas, and placental expression changes in genes important for heart development. Hand1 has roles in both heart and placental development and is implicated in CHDs including double right outlet, hypoplastic left heart syndrome, and septal defects; however, Hand1 involvement in placental vascularization and development is under-investigated. We utilized the Hand1A126fs/+ murine model to investigate Hand1 in placentation and vascularization.MethodsHand1A126fs/+ female mice were time-mated with Nkx2.5cre (placenta- and heart-specific) males to produce either Nkx2.5cre;Hand1+/+ or Nkx2.5cre;Hand1A126fs/+ fetuses. Feto-placental units were harvested at timepoints from E8.5 to E14.5 for histological analysis; vascular assessment by immunohistochemistry for Hand1, CD-31, and CK-7; and angiogenesis by qPCR.ResultsEmbryonic lethality occurs in Nkx2.5cre/Hand1A126fs/+ by E14.5 due to a failure of placental labyrinth formation and vascularization. Chorionic trophoblasts did not form, although trophoblast giant cell subtypes were present. Fetal vessels failed to develop properly and were significantly lower in the labyrinth by day E12.5. Placental growth factor levels were significantly increased, and Angiopoietin2 expression trended higher in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates.ConclusionWe demonstrate that Hand1 expression in placental chorion and trophoblast is necessary for proper patterning of the labyrinth and vascularization within the labyrinth. Multiple angiogenic factors known to be expressed in trophoblast were disrupted in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates. Alterations in Hand1 expression represent a potential mechanism for abnormal placentation and early miscarriage in cases of CHD.

scholarly journals Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries

2018 ◽  
Author(s):  
Weston Troja ◽  
Kathryn J. Owens ◽  
Jennifer Courtney ◽  
Andrea C. Hinton ◽  
Robert B. Hinton ◽  
...  
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Fetal Growth ◽  
Weight Ratio ◽  
Growth Patterns ◽  
Left Heart ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Terminal Villi ◽  
And Function ◽  
Left Heart Syndrome

AbstractBackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD.MethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups.ResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Need to include RNA and IHC.ConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the

scholarly journals A Potential Role and Contribution of Androgens in Placental Development and Pregnancy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 644
Author(s):  
Agata M. Parsons ◽  
Gerrit J. Bouma
Keyword(s):  
Fetal Development ◽  
Fetal Loss ◽  
Membrane Receptors ◽  
Placental Development ◽  
Placental Function ◽  
Fetal Physiology ◽  
Estrogen Synthesis ◽  
And Function ◽  
Pregnancy Disorders

Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.

scholarly journals The Relationship Between Bullying Victimization and Perpetration and Non-suicidal Self-injury: A Systematic Review

2021 ◽  
Author(s):  
Gianluca Serafini ◽  
Andrea Aguglia ◽  
Andrea Amerio ◽  
Giovanna Canepa ◽  
Giulia Adavastro ◽  
...  
Keyword(s):  
Peer Victimization ◽  
Significant Risk ◽  
Positive Association ◽  
Significant Risk Factor ◽  
Future Research ◽  
Bullying Victimization ◽  
Self Injury ◽  
Long Run ◽  
Bully Victims

AbstractExperience of bullying may be a significant risk factor for non-suicidal self-injury (NSSI). This study had three aims: to systematically investigate the association between bullying and NSSI, analyze the possible mechanisms underlying the two phenomena, and evaluate any differences between bullying victimization and bullying perpetration with respect to NSSI. A systematic search about the association between bullying victimization and perpetration and NSSI was conducted using specific databases (PubMed, Scopus, Science Direct). The following keywords were used in all database searches: "bullying" AND "NSSI" OR "peer victimization" and NSSI. The searches in PubMed, Scopus and Science Direct revealed a total of 88 articles about bullying or peer victimization and NSSI. However, only 29 met our inclusion criteria and were used for the present review. Overall, all studies examined victimization; four studies also evaluated the effects of perpetration and one included bully-victims. According to the main findings, both being a victim of bullying and perpetrating bullying may increase the risk of adverse psychological outcomes in terms of NSSI and suicidality in the short and the long run. To the best of our knowledge, this is the first review to systematically evaluate the relation between bullying victimization/perpetration and NSSI. The main results support a positive association. Future research should evaluate the possible role of specific mediators/moderators of the association between experience of bullying and NSSI.

Hypoplastic Left Heart Syndrome: Natural History in a Geographically Defined Population

PEDIATRICS ◽  
1990 ◽  
Vol 85 (6) ◽  
pp. 977-983
Author(s):  
Cynthia D. Morris ◽  
Jacquelyn Outcalt ◽  
Victor D. Menashe
Keyword(s):  
Natural History ◽  
Hypoplastic Left Heart Syndrome ◽  
Congenital Heart ◽  
Heart Defects ◽  
Norwood Procedure ◽  
Secular Change ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
History Of ◽  
Left Heart Syndrome

Advances in surgical treatment of hypoplastic left heart syndrome with the Norwood procedure and cardiac transplantation have made essential the understanding of the natural history of hypoplastic left heart syndrome. In a geographically defined population, we ascertained the prevalence of hypoplastic left heart syndrome in children born in Oregon from 1971 through 1986. Clinical and anatomic data were extracted from the charts of the 98 affected children and the survival rate was calculated. Hypoplastic left heart syndrome occurred in 0.162 per 1000 live births in Oregon during this period. No syndrome complex was prevalent and 84% were free of other congenital malformations. However, there was an increased occurrence of congenital heart defects in first-degree relatives of probands with hypoplastic left heart syndrome. Of the affected children 15 ± 4% died on the first day of life, 70 ± 5% died within the first week, and 91 ± 3% died within 30 days. No secular change in survival occurred during the study. Palliation with the Norwood procedure was performed in 20 children. Although survival was significantly improved with this surgery (P = .01), the effect was observed principally through 30 days of life and only one of these children remains alive. Hypoplastic left heart syndrome is a lethal congenital heart defect in children and poses management and ethical dilemmas.

The genetics of hypoplastic left heart syndrome

1999 ◽  
Vol 9 (6) ◽  
pp. 627-632 ◽  
Author(s):  
Paul D. Grossfeld
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Heart Defects ◽  
Left Ventricular ◽  
Left Ventricular Cavity ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Term Survival ◽  
Surgical Options ◽  
Systemic Ventricle ◽  
Left Heart Syndrome

Hypoplastic left heart syndrome is one of the most therapeutically challenging congenital cardiac defects. It accounts for as many as 1.5% of all congenital heart defects, but is responsible for up to one quarter of deaths in neonates with heart disease.1The management of hypoplastic left heart syndrome is controversial. Two surgical options exist:2,3the Norwood procedure, is a three stage repair in which the morphologically right ventricle is converted to function as the systemic ventricle. Alternatively, orthotopic transplantation can be performed. Although both surgical options have had improved outcomes, the prognosis for long-term survival is guarded, with a five year survival for either approach reported to be in the region of 50–60%. In this review, I explore the evidence for a genetic etiology for the “classic” hypoplastic left heart syndrome, defined as mitral and/or aortic atresia with hypoplasia of the left ventricular cavity and the other left-sided structures.

scholarly journals Novel Insights Into RV Adaptation and Function in Hypoplastic Left Heart Syndrome Between the First 2 Stages of Surgical Palliation

2011 ◽  
Vol 4 (2) ◽  
pp. 128-137 ◽  
Author(s):  
Nee Scze Khoo ◽  
Jeffrey F. Smallhorn ◽  
Sachie Kaneko ◽  
Kimberly Myers ◽  
Shelby Kutty ◽  
...  
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Surgical Palliation ◽  
And Function ◽  
Left Heart Syndrome

scholarly journals Umbilical Neutrophil Gelatinase-Associated Lipocalin Level as an Early Predictor of Acute Kidney Injury in Neonates with Hypoplastic Left Heart Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Piotr Surmiak ◽  
Małgorzata Baumert ◽  
Małgorzata Fiala ◽  
Zofia Walencka ◽  
Andrzej Więcek
Keyword(s):  
Acute Kidney Injury ◽  
Hypoplastic Left Heart Syndrome ◽  
Heart Defects ◽  
Kidney Injury ◽  
High Sensitivity ◽  
Left Heart ◽  
Acid Base Balance ◽  
Hypoplastic Left Heart ◽  
Umbilical Blood ◽  
Left Heart Syndrome

Acute kidney injury (AKI) is a primarily described complication after unbalanced systemic perfusion in neonates with congenital heart defects, including hypoplastic left heart syndrome (HLHS). The aim of the study was to compare the umbilical NGAL concentrations between neonates born with HLHS and healthy infants, as well as to analyze whether the determination of NGAL level could predict AKI in neonates with prenatally diagnosed HLHS. Twenty-one neonates with prenatally diagnosed HLHS were enrolled as study group and 30 healthy neonates served as controls. Perinatal characteristics and postnatal parameters were extracted from the hospital neonatal database. In umbilical cord blood, we determined plasma NGAL concentrations, acid base balance, and lactate and creatinine levels. In neonates with HLHS, complications (respiratory insufficiency, circulatory failure, NEC, IVH, and AKI) were recorded until the day of cardiosurgery. We observed in neonates with HLHS higher umbilical NGAL levels compared to controls. Among 8 neonates with HLHS and diagnosed AKI stage 1, we observed elevated NGAL levels in comparison to those newborns without AKI. Umbilical NGAL could predict, with high sensitivity and specificity, AKI development in study neonates. We suggest that the umbilical blood NGAL concentration may be an early marker to predict AKI in neonates with HLHS.

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