Conditional Mutation of Hand1 in the Mouse Placenta Disrupts Placental Vascular Development Resulting in Fetal Loss in Both Early and Late Pregnancy

Congenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. We have previously demonstrated abnormal placental vascularization in human placentas from fetuses diagnosed with CHD. Hand1 has roles in both heart and placental development and is implicated in CHD development. We utilized two conditionally activated Hand1A126fs/+ murine mutant models to investigate the importance of cell-specific Hand1 on placental development in early (Nkx2-5Cre) and late (Cdh5Cre) pregnancy. Embryonic lethality occurred in Nkx2-5Cre/Hand1A126fs/+ embryos with marked fetal demise occurring after E10.5 due to a failure in placental labyrinth formation and therefore the inability to switch to hemotrophic nutrition or maintain sufficient oxygen transfer to the fetus. Labyrinthine vessels failed to develop appropriately and vessel density was significantly lower by day E12.5. In late pregnancy, the occurrence of Cdh5Cre+;Hand1A126fs/+ fetuses was reduced from 29% at E12.5 to 20% at E18.5 and remaining fetuses exhibited reduced fetal and placental weights, labyrinth vessel density and placenta angiogenic factor mRNA expression. Our results demonstrate for the first time the necessity of Hand1 in both establishment and remodeling of the exchange area beyond early pregnancy and in patterning vascularization of the placental labyrinth crucial for maintaining pregnancy and successful fetal growth.

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106 ANGIOGENIC FACTOR mRNA EXPRESSION IN FETAL MEMBRANES IN EARLY PREGNANT SHEEP

Reproduction Fertility and Development ◽

10.1071/rdv21n1ab106 ◽

2009 ◽

Vol 21 (1) ◽

pp. 153

Author(s):

M. L. Johnson ◽

L. P. Reynolds ◽

M. A. Minten ◽

P. P. Borowicz ◽

D. A. Redmer ◽

...

Keyword(s):

Growth Factor ◽

Vascular Development ◽

Fetal Loss ◽

Angiogenic Factor ◽

Fetal Membranes ◽

Detailed Knowledge ◽

Placental Development ◽

Vegf Mrna ◽

Placental Angiogenesis ◽

Pregnant Sheep

Maternal and fetal placental development may be compromised by use of assisted reproductive techniques, including cloning, resulting in poor placental angiogenesis and subsequent high embryonic/fetal loss (Palmieri et al. 2007 Placenta 28, 577–584). Before changes in vascular development in placenta from compromised pregnancies can be understood, a detailed knowledge of regulation of angiogenesis in placental tissues from normal pregnancies is necessary. Therefore, this study determined the expression pattern of mRNA for several angiogenic factors and their receptors: vascular endothelial growth factor (VEGF) and receptor (R) 1 and 2; basic fibroblast growth factor (FGF2) and FGFRIIIc; angiopoietin (ANGPT) 1 and 2 and ANGPTR (Tie2); endothelial nitric oxide synthase (eNOS) and NO receptor GUCY1B3 in fetal membranes (FM; fetal placenta) collected on Days 16, 18, 20, 22, 24, 26, 28, and 30 after mating (n = 5 to 8/day). Fetal membranes were snap frozen for evaluation of gene expression using quantitative, real-time RT-PCR. VEGF mRNA was increased (P < 0.05) 2-fold on Days 28 and 30 compared with Days 16, 18, and 20, whereas VEGFR1 mRNA increased (P < 0.05) 25- to 50-fold on Days 28 and 30 compared with Day 16, and VEGFR2 mRNA was greatest (P < 0.05) on Day 22 compared with Days 16, 18, 28, and 30. FGF2 mRNA was 4-fold greater (P < 0.05) on Day 22 compared with Day 16; however, FGF2RIIIc was unchanged from Day 16 through 30. eNOS mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18, but GUCY1B3 mRNA was greatest (P < 0.05) on Day 18 compared with Days 20, 24, and 28. ANGPT1 mRNA increased (P < 0.05) 40-fold by Days 28 and 30 compared with Days 16 and 18. ANGPT2 mRNA was undetectable on Day 16, and increased (P < 0.05) 5-fold from Days 18 through 30. ANGPTR mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18. This description of expression of factors potentially regulating early placental angiogenesis during normal pregnancy in sheep will provide the foundation for understanding the dramatic increases in capillary cell proliferation and capillary size we have previously observed (unpublished) and for determining whether placental vascular development is altered in compromised pregnancies. USDA-NRI grant 2007-01215 to LPR and ATGB; NIH grant HL64141 to LPR and DAR; ND EPSCoR AURA grant to ATGB and MAM; ND Space Grant Fellowship Program award to MAM; and NIH grant P20 RR016741 (INBRE program of the NCRR, NIH).

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

Life ◽

10.3390/life11070644 ◽

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.

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Abstract 18060: TRAIL Promotes Angiogenesis and Ischemia-Induced Neovascularisation via NOX4, H2O2 and Nitric Oxide-Dependent Mechanisms

Circulation ◽

10.1161/circ.130.suppl_2.18060 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Belinda A Di Bartolo ◽

Sian P Cartland ◽

Leonel Prado-Lourenco ◽

Nor Saadah M Azahri ◽

Thuan Thai ◽

...

Keyword(s):

Nitric Oxide ◽

Angiogenic Factor ◽

Tubule Formation ◽

Nitric Oxide Synthase Inhibitor ◽

Therapeutic Implications ◽

Synthase Inhibitor ◽

Oxide Synthase ◽

First Time

Background: Angiogenesis and neovascularization are essential processes that follow ischemia insults. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) not only induces endothelial cell (EC) death and inhibits angiogenesis, but also promotes EC migration, invasion and proliferation in vitro . These seemingly opposite effects make its role in angiogenesis in vivo unclear. Using TRAIL -/- and wild-type mice, we sought to determine the role of TRAIL in angiogenesis and neovascularisation. We also sought mechanisms in vitro . Methods and Results: Reduced vascularisation assessed by real-time in vivo 3D Vevo ultrasound imaging and CD31 staining was observed in TRAIL -/- mice 28 d after hindlimb ischemia. Moreover, reduced capillary formation and increased apoptosis was evident in TRAIL -/- muscles even at 3 d after ischemic surgery. We have previously shown that fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, regulates TRAIL gene expression in vascular smooth muscle cells. Indeed, FGF-2 also regulates TRAIL expression in ECs, and FGF-2-inducible proliferation, migration and tubule formation was inhibited with siRNA targeting TRAIL. Notably, both FGF-2 and TRAIL significantly increased NOX4 expression. TRAIL-inducible angiogenic activity in ECs was inhibited with siRNAs targeting NOX4, and consistent with these, NOX4 mRNA was reduced in 3 d ischemic hindlimbs of TRAIL -/- mice. TRAIL stimulated intracellular H 2 O 2 levels in ECs, and TRAIL-inducible proliferation, migration and tubule formation was inhibited with not only PEG-catalase, a H 2 O 2 scavenger, but also blocked with L-NAME, a nitric oxide synthase inhibitor. Conclusions: This is the first demonstration showing that TRAIL promotes angiogenesis in vivo . We show for the first time that the TRAIL stimulates NOX4 expression to mediate nitric oxide-dependent angiogenic effects. This has significant therapeutic implications such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with CVD and diabetes.

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Expression of a hypomorphic Pomc allele alters leptin dynamics during late pregnancy

Journal of Endocrinology ◽

10.1530/joe-19-0576 ◽

2020 ◽

Vol 245 (1) ◽

pp. 115-127 ◽

Cited By ~ 1

Author(s):

Hui Yu ◽

Zoe Thompson ◽

Sylee Kiran ◽

Graham L Jones ◽

Lakshmi Mundada ◽

...

Keyword(s):

Fat Mass ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Late Pregnancy ◽

Placental Development ◽

Hypomorphic Mutation ◽

Protein Levels ◽

Maximal Arc ◽

Hypothalamic Arcuate Nucleus ◽

Pregnancy And Lactation

Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.

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Angiogenic factor abnormalities and fetal demise in a twin pregnancy

Nature Reviews Nephrology ◽

10.1038/nrneph.2009.154 ◽

2009 ◽

Vol 5 (11) ◽

pp. 658-662 ◽

Cited By ~ 10

Author(s):

Michelle A. Hladunewich ◽

Guy Steinberg ◽

S. Ananth Karumanchi ◽

Richard J. Levine ◽

Sarah Keating ◽

...

Keyword(s):

Twin Pregnancy ◽

Angiogenic Factor ◽

Fetal Demise

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Abstract 17312: Hand1 Impairs Angiogenesis in Heart and Placenta

Circulation ◽

10.1161/circ.138.suppl_1.17312 ◽

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.

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Abstract MP20: Prepartum 1,3-butanediol Treatment Improves Placental Perfusion In The Preeclamptic Dahl Salt-sensitive Rat

Hypertension ◽

10.1161/hyp.76.suppl_1.mp20 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Jeanne Ishimwe ◽

Michael R Garrett ◽

Jennifer M Sasser

Keyword(s):

Resistance Index ◽

Kidney Injury ◽

Late Pregnancy ◽

Treated Group ◽

Chronic Hypertension ◽

Fetal Demise ◽

Pilot Studies ◽

Placental Perfusion ◽

And Control ◽

Placental Ischemia

Chronic hypertension increases the risk of developing superimposed preeclampsia (PE). Previous reports showed that 1,3-Butanediol (BD) lowers blood pressure (BP) in male Dahl salt-sensitive (S) rats and female congenic S.SHR(11) rats which exhibit increased kidney injury over Dahl S rats. The goal of this study was to test if attenuating hypertension before pregnancy through the placentation period via BD prevents the onset of PE. Female Dahl S rats (a spontaneous model of superimposed PE, 11-16 weeks old) were divided into two groups: BD treated (20% via drinking water) and control (ad libitum water). Animals received BD for 7 weeks, baseline BP measurements (telemetry) were taken, and both groups were then mated. On gestation day (GD) 12, treatment was stopped because pilot studies showed that treatment reduced water intake during late pregnancy. Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n=8/group). At GD18 (late pregnancy), uterine artery resistance index (UARI) was measured via Doppler ultrasound, 24h urine was collected on GD19, and tissues were harvested on GD20. Mean arterial pressure was lower in the treated group at baseline (141.9 ± 4.1 vs. 165.7 ± 4.5 mmHg, p= 0.008), early (135.9 ± 3.4 vs. 168.9 ± 4.6 mmHg, p= 0.0003), mid (142.0 ± 5.2 vs. 170.8 ± 4.61, p= 0.0048) but not late pregnancy (144.9 ± 5.9 vs. 161.9 ± 4.5 mmHg, p= 0.165). Late pregnancy maternal body weight was similar between groups (299.3 ± 5.6 vs. 311.3 ±7.0 g, p=0.201). Treated dams had a lower UARI (0.71 ± 0.02 vs. 0.81 ± 0.02, p=0.008) and less fetal resorptions (1.12 ± 0.29 vs. 2.25 ± 0.41, p= 0.043). No harm to the fetus was noted as no differences in pup weight (2.20 ±0.05 vs. 2.20 ± 0.09, p= 0.994) and pup length (30.19 ±0.24 vs. 29.45 ± 0.28 cm, p=0.072) were observed. Placentas from treated dams had decreased VEGF levels via ELISA (276.2 ± 33.4 vs. 498.9 ± 16.8 pg/mL, p= 0.001), suggesting reduced placental ischemia. In this study, we observed slightly improved placental perfusion and lower fetal demise following prepartum BD treatment; however, the antihypertensive effects of BD were not sustained through late pregnancy when supplementation was stopped at mid-pregnancy.

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Decidual glycodelin-A polarizes human monocytes into a decidual macrophage-like phenotype through Siglec-7

Journal of Cell Science ◽

10.1242/jcs.244400 ◽

2020 ◽

Vol 133 (14) ◽

pp. jcs244400 ◽

Cited By ~ 1

Author(s):

Madhavi Vijayan ◽

Cheuk-Lun Lee ◽

Vera H. H. Wong ◽

Xia Wang ◽

Kungfeng Bai ◽

...

Keyword(s):

Sialic Acid ◽

Immune Cell ◽

Fetal Loss ◽

Cell Types ◽

Dependent Manner ◽

Human Monocytes ◽

Placental Development ◽

Cell Functions ◽

Surface Marker Expression ◽

Glycodelin A

ABSTRACTDecidual macrophages constitute 20–30% of the total leukocytes in the uterus of pregnant women, regulating the maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages (dMs) are associated with fetal loss and pregnancy complications, such as preeclampsia. Monocytes differentiate into dMs in a decidua-specific microenvironment. Despite their important roles in pregnancy, the exact factors that regulate the differentiation into dMs remain unclear. Glycodelin-A (PAEP, hereafter referred to as GdA) is a glycoprotein that is abundantly present in the decidua, and plays an important role in fetomaternal defense and placental development. It modulates the differentiation and activity of several immune cell types residing in the decidua. In this study, we demonstrated that GdA induces the differentiation of human monocytes into dM-like phenotypes in terms of transcriptome, cell surface marker expression, secretome, and regulation of trophoblast and endothelial cell functions. We found that Sialic acid-binding Ig-like lectin 7 (Siglec-7) mediates the binding and biological actions of GdA in a sialic acid-dependent manner. We, therefore, suggest that GdA, induces the polarization of monocytes into dMs to regulate fetomaternal tolerance and placental development.

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Detection of antitrophoblast antibodies in the sera of patients with anticardiolipin antibodies and fetal loss

Blood ◽

10.1182/blood.v82.9.2730.2730 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2730-2741 ◽

Cited By ~ 35

Author(s):

KR McCrae ◽

AM DeMichele ◽

P Pandhi ◽

MJ Balsai ◽

P Samuels ◽

...

Keyword(s):

Fetal Loss ◽

Thromboxane A2 ◽

First Trimester ◽

Anticardiolipin Antibodies ◽

Trophoblast Cells ◽

Fetal Demise ◽

Blood Fluidity ◽

Increased Risk ◽

History Of ◽

Placental Blood

Abstract Women with anticardiolipin antibodies (ACLA) are at increased risk for fetal loss. One potential explanation for this outcome is that sera from these individuals contain antibodies reactive with trophoblast cells, which are involved in the establishment of the uteroplacental vasculature and maintenance of placental blood fluidity. To examine this hypothesis, we compared the incidence of trophoblast-reactive antibodies in 27 patients with ACLA and a history of fetal loss with that in 29 normal pregnant women. Sera from 20 patients, but only one control, contained trophoblast-reactive antibodies (P < .001). These antibodies were not directed against major histocompatibility class I antigens, and reacted with both term and first-trimester trophoblast cells. In most cases, sera from which ACLA were adsorbed by cardiolipin- containing liposomes maintained reactivity against cells. In addition, patient Ig fractions immunoprecipitated an approximately 62-kD protein from the trophoblast cell surface, stimulated the release of arachidonic acid and thromboxane A2 by trophoblasts, and inhibited the binding of prourokinase to trophoblast urokinase receptors. These observations show that sera from women with ACLA and a history of fetal loss contain antitrophoblast antibodies. These antibodies may be serologically distinct from ACLA, and may contribute to the pathogenesis of fetal demise.

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Blunt abdominal trauma with uterine rupture and fetal demise

Trauma ◽

10.1177/1460408616681601 ◽

2016 ◽

Vol 19 (3) ◽

pp. 219-221 ◽

Cited By ~ 1

Author(s):

Christina Lien ◽

Aamna Ali ◽

John Culhane

Keyword(s):

Abdominal Trauma ◽

Blunt Abdominal Trauma ◽

Uterine Rupture ◽

Motor Vehicle ◽

Seat Belt ◽

Fetal Loss ◽

Fetal Demise ◽

Vehicle Accidents ◽

Pelvic Injuries ◽

Minor Injuries

Traumatic uterine rupture is rare, occurring in 0.6% of blunt trauma cases, and usually results from very violent accidents in which patients usually also sustain other major injuries. Following severe blunt abdominal trauma, fetal loss can result from maternal hypotension or hypoxemia, placental abruption, maternal death, and uterine rupture. Although less common, fetal loss can also occur in minor injuries. We report a patient who sustained an isolated anterior uterine rupture with fetal demise without any associated abdominal or pelvic injuries. This case report highlights the importance of proper seat belt usage and placement because both can reduce maternal and fetal morbidity and mortality in motor vehicle accidents.

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