Pre Eclampsie / Eclampsie
Study conducted by Vassilis Tsatsaris - Cochin Hospital Group, AP-HP, Maternity Port-Royal, 75014 Paris, France Inserm Unit U767, Paris, F-75006, France, Paris Descartes University, 75006 Paris, France.
I was not part of the study team but I'm sharing the results, this week, because Eclampsia / Preeclampsia remain a serious pathology and a terrible women killer in most countries in the world .This Recent work has led to a better understanding of the pathology's physiopathology with the hope of setting up new screening tools and possible therapeutic perspectives.
Summary:
Preeclampsia is a complication of pregnancy Identified by the association of high blood pressure, proteinuria and edema. This is a pathology specific to human pregnancy, occurring in the third trimester (can be seen as of 20 weeks of gestation). Secondary to a placental dysfunction ending up in a release, in the maternal circulation, of various substances responsible for the activation of maternal endothelial lesions. High blood pressure, glomerular nephropathy and an increase vascular permeability are all consequences of those lesions.
Introduction:
Pre-eclampsia is an maternal endothelium disease whose origin is placental. It is specific to female human being and to the gestation. In fact, there is no spontaneous pre-eclamptic syndrom in animals, which does not facilitate the understanding of its physiopathology. Reason why the pathophysiology of preeclampsia remains imperfectly understood. However recent molecular datas confronted to older pathological studies point to a pathophysiological schema in two stages: 1-) A pre-clinical stage corresponding to placental insufficiency often related to an abnormal development of the placenta in its very early stages. 2-) The second phase , the clinic that corresponds to a maternal endothelium dysfunction linked to various substances released by the placenta inside the maternal circulation ( free radicals , oxidized lipids, cytokines, sVEGFR-1, Soluble endoglines).
1-) The preclinical phase: Placental dysfunction
Human placentation is characterized by an invasion process inside the superficial uterine layer (decidua and myometrium) by extra-villous cytotrophoblasts. This trophoblastic invasion is directed towards spiral arteries of the uterus. This results in an invasion of the arterial wall that leads to a total disappearance of the smooth arterial muscular tunic and endothelial cells, which are replaced by the extra-villous trophoblast. The tunic of the arteries becomes sluggish, insensitive to the vasoactive elements thus allowing a facilitated infusion of the inter-villous chamber. Furthermore, trophoblastic cells, villous and extra-villous, produce powerful angiogenic agents that are responsible for a deep remodelling of the whole vascular architecture of the uterus.
During preeclampsia, the remodelling of the uterine vascular wall is altered with a particular defect of trophoblastic invasion. The invasion of the interstitial portion of the uterus is relatively preserved, but the one related to the endo and perivascular uterine arteries is greatly diminished. At this lack of maternal arteries invasion is added a defect of their remodelling by extra-villous cytotrophoblasts. Endothelial cells had not been replaced by trophoblasts and the layer of smooth muscle cells is not overhauled. Thus the uterine arteries, in the context of preeclampsia, have smaller diameters and retain their vasoconstriction potential leading to placental hypoxia. The study of the factors responsible for the trophoblastic invasion defect is difficult because preeclampsia is merely diagnosed after the natural process of trophoblastic invasion. Consequently, the abnormalies observed in cases of preeclampsia do not establish if they are the cause or the consequence of this syndrome.
Recent studies have exploited fragments of chorionic villi obtained during trophoblastic and compatible biopsies with the continuation of the pregnancy. These villi have made it possible to study the expression of certain genes in women with normal pregnancy and in women who later developed pre-eclampsia. At 10 SA, 36 genes are expressed differentially between these two groups of women. Thirty-one of these genes are under-expressed among women who will develop pre-eclampsia and their function is involved in immunization, immune regulation and cell mobility. So the mechanisms allowing the trophoblastic semi-allogeneic cells to invade maternal tissues by foiling the maternal processes of recognition of non-self may prove to be faulty. One of the hypotheses about the etiology of preeclampsia relies on the activation of immune cells. In fact, during pregnancy, the non-recognition of trophoblasts by immune cells limits the activation of these protectors and therefore the lysis of trophoblasts of the deciduous. Conversely, during preeclampsia, the number of immune cells activated would increase. A study recently reveals an inverse distribution of trophoblasts and macrophages at the level of the uterine arteries wall of pre-eclamptic patients compared to patients with normal pregnancy. Therefore, macrophages are very little present when trophoblastic arterial invasion is proceeding normally. Conversely, the number of activated macrophages increases in the uterine artery wall of pre-eclamptic patients where very few extra-villous trophoblasts are present. On the other hand, apoptosis of extra-villous cytotrophoblasts increases in the vicinity of the arterial wall in case of preeclampsia. In fact, macrophages of the decidua produce and respond to a broad spectrum of cytokines and would be involved in paracrine mechanisms regulating the trophoblastic invasion.
Another defective system seems to be involved in the defect of invasion of the spiral arteries by the trophoblastic cells. This is the system HLA and in particular the expression of HLA-G. HLA-G and HLA-E protect cytotrophoblasts extra-villous and cytotoxic NK cells. It has been shown that the expression of HLA-G by trophoblastic cells extra-villous was absent or diminished in case of pre-eclampsia.
2-) Clinical phase:
Endothelial dysfunction secondary to soluble factors of the placenta released inside vascular area. Decrease in placental perfusion secondary to uterine poor vascular remodelling gradually generates a placental dysfunction. The cause of this dysfunction is currently poorly known and debated. It is conventionally admitted that it is the placental hypoxia but there is no currently direct evidence in favour of this hypoxia. In addition, the placenta in a complicated pregnancy with preeclampsia has markers of oxidative stress. In fact, stable metabolites of lipid peroxydation generated by oxidative stress are abnormally present and produced in pre-eclamptic placentas such as lipid peroxides and free isoprostane (8-iso-PGF 2%), a specific product of arachidonic acid catalysis done by free radicals with vasoconstrictor activities and platelets aggregation.
Oxidative stress inside the placenta seems to be partly responsible of physio- pathological changes leading to preeclampsia. In fact, it is responsible of an increase in placental apoptosis and the release of placental apoptotic debris in the maternal circulation. it is known that the syncytium is renewed during the pregnancy by the releasing of apoptotic debris in the maternal circulation. These debris induce a systemic inflammatory response completely normal during the pregnancy. Oxidative stress stimulates apoptosis syncytium as well as other tissues, and therefore increases the release of syncytial micro-villous membranes (STBM) and other syncytial debris in the maternal circulation, as observed in case of pre-eclampsia.
Huppertz reports that hypoxia promotes the release of fragments of placental syncytium inside maternal circulation by necrosis rather than apoptosis. The concept of "aponecrosis" of the syncytium is proposed: in hypoxic condition, the syncytium formation is blocked because of a lacking of RNA, protein and 'fresh' organelles cannot finish the apoptotic cascade and start therefore a secondary elimination by necrosis. This debris would further activate the inflammatory response involved in endothelial activation, specific to preeclampsia.
In agreement with this theory is the fact as the deportation of trophoblastic cells and syncytial fragments is superior in maternal uterine veins of preeclamptic patients. Syncytiotrophoblastics membranes Isolated in normal or pre-eclamptic placentas destroy and specifically inhibit proliferation of human endothelial cells in culture. Moreover, placental dysfunction generates other factors that are released in the maternal circulation and which are involved in maternal endothelial lesions.
Here are a non-exhaustive list of these factors: EGF , VEGF , sVEGFR-1 , sVEGFR-2 , Endogline soluble , TGF & et Beta , IGF-II , TNF , IL-1 , IL-6 , IL-10 , IFN , LIF , Prostaglandines et Lipides oxydés , des phospholipids , des Acides gras et Endothélines.
. Among Of these, two molecules seem to play a predominant role inside the pathophysiology of pre-eclampsia; these are the soluble receptor VEGF (sVEGFR-1 and sFLT-1) and endoglin soluble. Recent work has shown that VEGF plays an important role in the pathophysiology of endothelial dysfunctions during pre-eclampsia. VEGF and PlGF are growth factors involved in the processes of angiogenesis and vasculogenesis. These are essential factors for endothelial cells survival. During the normal pregnancy, the trophoblastic cell secrets a soluble form of the receptor VEGF type 1 called sFLT-1, which is released in the maternal circulation. The sFLT-1binds to VEGF and PlGF and behaves so as a competitive antagonist of these molecules. The SFLT-1 unit for VEGF is larger than for the PlGF, which explains that during normal pregnancy serum levels of free VEGF are reduced whereas serum levels of PlGF are relatively preserved. In case of preeclampsia, probably because of placental hypoxia,placental production of sFLT-1 is considerably increased resulting in an undeniable serum levels of VEGF and PlGF. It has been shown that a deficiency in VEGF and PlGF is responsible for endothelial dysfunction and maternal systemic glomerular nephropathy
More recently the role of soluble endoglin, another soluble receptor, was put prominently in the pathophysiology of endothelial dysfunction of preeclampsia. Endoglin (Eng) or CD105 is a membrane receptor for isoforms 1 and 3 transforming growth factor & (TGF & 1 and TGF & 3). This receptor is strongly expressed at the level of endothelial cells and at syncytiotrophoblast level. The endoglin soluble is also involved in the occurrence
HELLP syndrome. Increasing of sFLT-1 and sEng is early and occurs well before the appearance of clinical signs of Preeclampsia. So they open new hopes for early serum screening of preeclampsia allowing to consider a primary prevention of this pathology.
Conclusion
Preeclampsia is a maternal pathology, specific to human pregnancy, secondary to placental dysfunction. The causes responsible for this placental dysfunction are in fact very variable, which makes the experimental approach of this pathology very complex. This placental dysfunction is responsible for the release into the maternal circulation substances that induce endothelial dysfunction characterized by activation of endothelial cells and an increase in vascular permeability. Two molecules produced by the placenta play a crucial role in the pathophysiology of preeclampsia; these are the sFLT-1 and soluble endoglin. The Work on these two molecules open new research pathways on screening and probably the treatment of preeclampsia.
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