Altered feto-placental vascularization, feto-placental malperfusion, and fetal growth restriction in mice with Egfl7 loss-of-function

Lacko, Lauretta A.; Hurtado, Romulo; Hinds, Samantha; Poulos, Michael G.; Butler, Jason M.; Stuhlmann, Heidi

doi:10.1242/dev.147025

Cited by 31 publications

(23 citation statements)

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“…Finally, our EAE data in a new inducible EGFL7-KO restricted to the endothelium that spares miR-126/miR-126* demonstrate that EAE worsening in the absence of EGFL7 is independent of its expression in non-endothelial cells, of developmental abnormalities, and of the expression of miR-126/miR-126*. Indeed, recent data supports the hypothesis that EGFL7 mediates its vascular effects beyond the functions of miR-126/miR-126* 37 .…”

Section: Discussionsupporting

confidence: 74%

EGFL7 reduces CNS inflammation in mouse

et al. 2018

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Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand αvβ3 integrin and can adhere to EGFL7 through integrin αvβ3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS.

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Section: Discussionsupporting

confidence: 74%

EGFL7 reduces CNS inflammation in mouse

et al. 2018

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“…; Lacko et al . ). Based on immunohistochemical CD34 and eNOS staining, as well as immunoblotting of CD31 of E18.5 placenta, the vascular density was reduced in HFD but recovered by exercise training (Fig.…”

Section: Resultsmentioning

confidence: 97%

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Son

Liu

Tian

et al. 2019

The Journal of Physiology

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Key pointsr Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet.r Exercise intervention of obese mothers prevents fetal overgrowth. r Exercise intervention reverses impaired placental vascularization in obese mice. r Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity.Abstract More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO-induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP-activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was Jun Seok Son received MS Degree in Kinesiology from Seoul National University. Currently, Jun Seok is a PhD student in the . His research interests focus on the impacts of maternal obesity, exercise, nutrition and other physiological conditions on fetal development and offspring health, especially the epigenetic mechanisms linking nutrients/metabolites to progenitor cell differentiation into myocytes/adipocytes. Ultimately, he aims to translate his work into clinical practice with respect to improving health outcomes for mothers and children affected by obesity.

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“…The decreased fetal blood space and increased maternal blood space created a 60% higher maternal to fetal blood space ratio in the placentae from Δ9-THC exposed pregnancies, suggestive of impaired nutrient transport 91 . The changes in the ratio of maternal to fetal vascularity could be attributed to an overall defect in blood vessel formation given pregnant women who used cannabis at least once per month exhibited less expression of CD31 in the placenta, a marker of endothelial cells and thereby, indirectly, angiogenesis 12,91 . Moreover, treatment of pregnant mouse dams with 5 mg/kg i.p.…”

Section: Discussionmentioning

confidence: 99%

Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta

Natale

Gustin

Lee

et al. 2020

Sci Rep

145

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1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by postnatal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy. Over the last decade, cannabis use has progressively increased in pregnant women, in part due to the perception that its usage poses no risk in perinatal life 1,2. In the United States, the rates of self-reported or screened cannabis use in pregnant mothers (18-24 years) varies from 6 to 22%, with some women admitting to daily use 2,3. Of great concern is that cannabis use in pregnancy is more prevalent in young, urban, socially disadvantaged women 4,5 .

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Altered feto-placental vascularization, feto-placental malperfusion, and fetal growth restriction in mice with Egfl7 loss-of-function

Cited by 31 publications

References 50 publications

EGFL7 reduces CNS inflammation in mouse

EGFL7 reduces CNS inflammation in mouse

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta

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