Targeted Delivery of Epidermal Growth Factor to the Human Placenta to Treat Fetal Growth Restriction

Placental dysfunction is the underlying cause of pregnancy complications such as fetal growth restriction (FGR) and pre-eclampsia. No therapies are available to treat a poorly functioning placenta, primarily due to the risks of adverse side effects in both the mother and the fetus resulting from systemic drug delivery. The use of targeted liposomes to selectively deliver payloads to the placenta has the potential to overcome these issues. In this study, we assessed the safety and efficacy of epidermal growth factor (EGF)-loaded, peptide-decorated liposomes to improve different aspects of placental function, using tissue from healthy control pregnancies at term, and pregnancies complicated by FGR. Phage screening identified a peptide sequence, CGPSARAPC (GPS), which selectively homed to mouse placentas in vivo, and bound to the outer syncytiotrophoblast layer of human placental explants ex vivo. GPS-decorated liposomes were prepared containing PBS or EGF (50–100 ng/mL), and placental explants were cultured with liposomes for up to 48 h. Undecorated and GPS-decorated liposomes containing PBS did not affect the basal rate of amino acid transport, human chorionic gonadotropin (hCG) release or cell turnover in placental explants from healthy controls. GPS-decorated liposomes containing EGF significantly increased amino acid transporter activity in healthy control explants, but not in placental explants from women with FGR. hCG secretion and cell turnover were unaffected by EGF delivery; however, differential activation of downstream protein kinases was observed when EGF was delivered via GPS-decorated vs. undecorated liposomes. These data indicate that targeted liposomes represent a safe and useful tool for the development of new therapies for placental dysfunction, recapitulating the effects of free EGF.

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Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor

AJP Cell Physiology ◽

10.1152/ajpcell.2000.278.5.c982 ◽

2000 ◽

Vol 278 (5) ◽

pp. C982-C988 ◽

Cited By ~ 145

Author(s):

Roni Levy ◽

Steven D. Smith ◽

Kala Chandler ◽

Yoel Sadovsky ◽

D. Michael Nelson

Keyword(s):

Cell Differentiation ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Caspase Inhibitor ◽

Trophoblast Differentiation ◽

Epidermal Growth ◽

Induced Apoptosis

Preeclampsia and fetal growth restriction are associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes diminished trophoblast differentiation and enhanced apoptosis. We tested the hypothesis that hypoxia induces apoptosis in cultured trophoblasts, and that epidermal growth factor (EGF), an enhancer of trophoblast differentiation, diminishes hypoxia-induced apoptosis. Trophoblasts isolated from placentas of term-uncomplicated human pregnancies were cultured up to 72 h in standard ([Formula: see text]= 120 mmHg) or hypoxic ([Formula: see text] < 15 mmHg) conditions. Exposure to hypoxia for 24 h markedly enhanced trophoblast apoptosis as determined by DNA laddering, internucleosomal in situ DNA fragmentation, and histomorphology, as well as by the reversibility of the apoptotic process with a caspase inhibitor. Apoptosis was accompanied by increased expression of p53 and Bax and decreased expression of Bcl-2. Addition of EGF to cultured trophoblasts or exposure of more differentiated trophoblasts to hypoxia significantly lowered the level of apoptosis. We conclude that hypoxia enhances apoptosis in cultured trophoblasts by a mechanism that involves an increase in p53 and Bax expression. EGF and enhancement of cell differentiation protect against hypoxic-induced apoptosis.

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Absence of TRPC1 Ca2+-permeable Channel Causes Placental and Fetal Growth Restriction in Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab046_029 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 732-732

Author(s):

Kate Claycombe-Larson ◽

Amy Bundy ◽

James Roemmich ◽

Brij Singh

Keyword(s):

Growth Factor ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth And Development ◽

Branching Morphogenesis ◽

Growth Restriction ◽

Fetal Weight ◽

High Fat ◽

Vegf Mrna ◽

Placental Dysfunction

Abstract Objectives Placental tissue intracellular calcium (Ca2+) regulates placental development and growth (e.g., blastocyst development through branching morphogenesis). Maternal high-fat (HF) diet results in placental lipid accumulation, increase in inflammation, reduction in nutrient transport expression and intra uterine growth restriction (IUGR). Currently, whether maternal HF diet affects placental and fetal growth and development differentially under reduction in Ca2 + influx is not known. Thus, we hypothesized that maternal HF diet feeding decreases placental growth and development resulting in IUGR. We further hypothesized that reduction of Ca2 + influx in placenta worsens the maternal HF-induced placental dysfunction. Methods Two-month old female B6129SF2/J wild type (WT) and transient receptor potential canonical 1 (TRPC1) protein deficient (KO) mice were fed normal fat (NF, 16% fat) and high fat (HF, 45%) diets for 12 weeks. Fetuses and placentae were examined at mid- (D12) and late- (D19) gestation. Results Placental length, width, and weight as well as fetal weight were decreased in the TRPC1KO mice at D12 and D19 compared to that of WT mice. Expression of placental growth factor (PLGF) mRNA was decreased at D12 in TRPC1 KO mice while vascular endothelial growth factor (VEGF) mRNA levels were increased at D19 compared to WT mice. Conclusions These findings suggest that genotypic differences rather than maternal HF diet alter placental size and weight as well as fetal weight. Decreased in PLGF mRNA may be responsible for the placental and fetal growth restriction while increase in VEGF mRNA indicates compensatory adaptation to decreased PLGF-associated placental and fetal growth restriction. Future studies are needed to determine the signaling mechanism underlying Ca2 + influx reduction- induced placental dysfunction and IUGR. Funding Sources USDA Agricultural Research Service Project #3062–51,000-054–00D.

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