Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

Brouillet, Sophie; Hoffmann, P.; Chauvet, Sylvain; Salomón, A.; Chamboredon, Sandrine; Sergent, F.; Benharouga, Mohamed; Feige, Jean‐Jacques; Alfaidy, Nadia

doi:10.1007/s00018-011-0889-x

Cited by 63 publications

(68 citation statements)

References 52 publications

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“…5,29 Altogether our findings have demonstrated that EG-VEGF induces a PIH phenotype if maintained beyond the first trimester of pregnancy and provides evidence to suggest that maintenance of elevated EG-VEGF during the second and third trimesters of pregnancy contributes to the attenuation of this pathogenesis. These in vivo observations are consistent with our previous studies using human tissues during normal pregnancy 11,16,31,32 and also in pathological pregnancies. 9,12,13 Therefore, this study provides novel insights into the fine role of EG-VEGF in the development of PIH and the attenuation of its pathological symptoms, once the pathology is established.…”

Section: Discussionsupporting

confidence: 93%

Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

et al. 2016

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P regnancy-induced hypertension (PIH) complicates 6% to 10% of pregnancies.1 It represents 1 of the following 4 conditions: (1) pre-existing hypertension, (2) gestational hypertension and preeclampsia; (3) pre-existing hypertension plus superimposed gestational hypertension with proteinuria; and (4) unclassifiable hypertension. Among these conditions, preeclampsia entails severe consequences for both the mother and the fetus. 2,3During the first trimester of human pregnancy, the extravillous trophoblasts must migrate and invade the maternal decidua and differentiate to facilitate the uterine spiral arterioles to undergo transformation and widen their luminal diameter, thus supplying more blood containing oxygen and nutrients to the placenta and growing fetus. One of the major contributing factors to the development of PIH is the failure of the extravillous trophoblast invasion deep into the maternal decidua, Abstract-Pregnancy-induced hypertension diseases are classified as gestational hypertension, preeclampsia, or eclampsia. The mechanisms of their development and prediction are still to be discovered. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor secreted by the placenta during the first trimester of human pregnancy that was shown to control trophoblast invasion, to be upregulated by hypoxia, and to be abnormally elevated in pathological pregnancies complicated with preeclampsia and intrauterine growth restriction. These findings suggested that sustaining EG-VEGF levels beyond the first trimester of pregnancy may contribute to pregnancy-induced hypertension. To test this hypothesis, osmotic minipumps delivering EG-VEGF were implanted subcutaneously into gravid OF1 (Oncins France 1) mice on day 11.5 post coitus, which is equivalent to the end of the first trimester of human pregnancy. Mice were euthanized at 15.5 and 18.5 days post coitus to assess (1) litter size, placental, and fetal weights; (2) placental histology and function; (3) maternal blood pressure; (4) renal histology and function; and (5) circulating soluble fms-like tyrosine kinase 1 and soluble endoglin. Increased EG-VEGF levels caused significant defects in placental organization and function. Both increased hypoxia and decreased trophoblast invasion were observed. Treated mice had elevated circulating soluble fms-like tyrosine kinase 1 and soluble endoglin and developed gestational hypertension with dysregulated maternal kidney function. EG-VEGF effect on the kidney function was secondary to its effects on the placenta as similarly treated male mice had normal kidney functions. Altogether, these data provide a strong evidence to confirm that sustained EG-VEGF beyond the first trimester of pregnancy contributes to the development of pregnancy-induced hypertension. (Hypertension. 2016;68:148-156.

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Section: Discussionsupporting

confidence: 93%

Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

et al. 2016

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“…Expression of the immunoinhibitor CD274 was shown to be low in early first trimester and to increase around the onset of the second trimester (18). A different regulation in trophoblastic endocrine gland-derived (EG) vascular endothelial growth factor (VEGF) secretion by hCG via EG-VEGF receptors was also reported between early and late first-trimester placentas (6).…”

Section: Discussionmentioning

confidence: 96%

Comparative expression of hCG β-genes in human trophoblast from early and late first-trimester placentas

Cocquebert

Berndt

Segond

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Human chorionic gonadotropin (hCG) displays a major role in pregnancy initiation and progression and is involved in trophoblast differentiation and fusion. However, the site and the type of dimeric hCG production during the first trimester of pregnancy is poorly known. At that time, trophoblastic plugs present in the uterine arteries disappear, allowing unrestricted flow of maternal blood to the intervillous space. The consequence is an important modification of the trophoblast environment, including a rise of oxygen levels from about 2.5% before 10 wk of amenorrhea (WA) to ∼8% after 12 WA. Two specific β-hCG proteins that differ from three amino acids have been described: type 1 (CGB7) and type 2 (CGB3, -5, and -8). Here, we demonstrated in situ and ex vivo on placental villi and in vitro in primary cultures of human cytotrophoblasts that type 1 and 2 β-hCG RNAs and proteins were expressed by trophoblasts and that these expressions were higher before blood enters in the intervillous space (8–9 vs. 12–14 WA). hCG was immunodetected in villous mononucleated cytotrophoblasts (VCT) and syncytiotrophoblast (ST) at 8–9 WA but only in ST at 12–14 WA. Furthermore, hCG secretion was fourfold higher in VCT cultures from 8–9 WA compared with 12–14 WA. Interestingly, VCT from 8–9 WA placentas were found to exhibit more fusion features. Taken together, we showed that type 1 and type 2 β-hCG are highly expressed by VCT in the early first trimester, contributing to the high levels of hCG found in maternal serum at this term.

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“…The effect of hCG on EG-VEGF expression is transcriptional and is mediated by a cAMP response element (CRE2) located at -383 bp within the EG-VEGF promoter region. [23]. Importantly, hCG regulation of EG-VEGF expression has also been reported in the ovary [3].…”

Section: Opinionmentioning

confidence: 92%

EG-VEGF: a key endocrine factor in placental development

Brouillet

Hoffmann

Feige

et al. 2012

Trends in Endocrinology & Metabolism

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Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

Cited by 63 publications

References 52 publications

Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

Sustained Endocrine Gland–Derived Vascular Endothelial Growth Factor Levels Beyond the First Trimester of Pregnancy Display Phenotypic and Functional Changes Associated With the Pathogenesis of Pregnancy-Induced Hypertension

Comparative expression of hCG β-genes in human trophoblast from early and late first-trimester placentas

EG-VEGF: a key endocrine factor in placental development

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