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

Abstract

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.

The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects

“…Recent studies from our group provided evidence for the direct role of a new placental angiogenic called prokineticin 1 (PROK1) in normal and FGR pregnancies (Hoffmann et al, 2006(Hoffmann et al, , 2009Brouillet et al, 2012bBrouillet et al, , 2013bMurthi et al, 2015;Sergent et al, 2016). Due to its similarities of action with VEGF (LeCouter et al, 2001), PROK1 is also called as endocrine gland derived-vascular endothelial growth factor (EG-VEGF).…”

“…Since its identification EG-VEGF has been associated with the control of placental angiogenesis during the first trimester of pregnancy and the reactivation of its receptors in the placenta of patients with pregnancy pathologies such as PE and FGR (Brouillet et al, 2010(Brouillet et al, , 2012a(Brouillet et al, , 2013a(Brouillet et al, , 2014aGarnier et al, 2015;Alfaidy, 2016;Sergent et al, 2016). The reactivation of angiogenic processes was meant to compensate for the associated deleterious vascularization.…”

Nouveaux regards sur la prééclampsie

“…L'historique de la découverte de ces facteurs est détaillé dans une excellente revue de 2011 [3]. D'autres molécules peuvent contribuer à l'effet pro-angiogénique nécessaire à une grossesse normale, comme récemment documenté pour le système PROK (prokinéticines)/ PROKR [4,47] (➜). L'atteinte vasculaire au cours de la grossesse, induirait l'ensemble des symptômes de la maladie.…”

“…Les lymphocytes T régulateurs (Treg) participent également à la régulation des interactions foeto-placentaires. Une étude récente a en effet comparé les différentes populations de leucocytes, sur des coupes paraffinées de placenta issus de 18 échantillons contrôles et de 11 échantillons de placenta increta/accreta 4 [21]. Dans ces cas pathologiques associés à une pénétration trop profonde des trophoblastes dans les tissus maternels, le nombre de lymphocytes Treg est augmenté (multiplié par 6,8), celui des cellules dendritiques étant, quant à lui, diminué (divisé par 2,32).…”

Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

“…We recently reported that a specific endocrine placental factor named endocrine gland-derived vascular endothelial growth factor (EG-VEGF) exhibits features of a potential marker of pathologic pregnancies, including preeclampsia (18). EG-VEGF is also called prokineticin-1 and represents the canonical member of a recently described family of cytokines, the prokineticin family (19,20).…”