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Résumé scientifique de Mme Le Dr Sophie Lorquet Imprimer
Prix Alice et Albert Netter 2011
Dr Sophie Lorquet (Liège)
Le récepteur soluble du VEGF dans la prééclampsie.

Preeclampsia (PE), a major cause of feto-maternal morbidity and mortality, affects 3-5% of pregnancies. It is characterized by an onset of hypertension and proteinuria (>0.3 g/24 h) after 20 weeks of gestation. PE is a complex disorder with a range of clinical presentations (PE, Hemolysis Elevated Liver enzyme and Low Platelet (HELLP syndrome), Eclampsia...). This heterogeneity suggests the possibility of varied pathogenic mechanisms. The initial etiologic factors are not well understood. Numbers of risk factors have been defined and two theories are mainly described: the vascular and the inflammatory theories. The first one postulates that defective placentation and invasion of the spiral arteries alone are responsible of the placental hypoxia, which is implicated in the endothelial dysfunction and the maternal symptoms. The inflammatory theory postulates that the placental hypoxia is necessary but not sufficient to cause PE. Indeed, a certain degree of oxidative stress and inflammation are needed to create the placental dysfunction responsible of the secretion of the different factors generating the maternal syndrome. Among these factors, we were particularly interested in the soluble Receptor-1 for the Vascular Endothelial Growth Factor (sVEGFR-1) and the soluble Endoglin (sEng), which are secreted in excess in PE.

Angiogenesis is essential for an efficient placentation. Among the different angiogenic factors, we were interested in the VEGF family members and its receptors. The two main receptors of VEGF implicated in angiogenesis, VEGFR-1 and VEGFR-2, belong to the class of tyrosin-kinase receptors. Beside these two membrane-bound receptors, a spliced variant of the transcript of VEGFR-1 leads to the secretion of a soluble form of the receptor. sVEGFR-1 is detected in the plasma of patients with PE or ischemia as well as in some cancers. During PE, sVEGFR-1 is secreted in huge amounts by the placenta and it is likely to cause the renal endotheliosis, which characterize PE and the endothelial dysfunction. A soluble form of the VEGFR-2, sVEGFR-2, has also been recently described in plasma from healthy people and from patients with leukemia or disseminated erythematous lupus. Its levels are decreased in patients with PE. Soluble Endoglin is a membrane-bound co-receptor for Transforming Growth Factors-1 and -3 (TGF-1 and -3). It is implicated in cardio-vascular development and vascular homeostasis, particularly by its interaction with endothelial Nitric Oxide Synthase (eNOS). sEng is an anti-angiogenic protein and is able to prevent TGF-1-dependant signalization in the vascular network. It has been recently described in sera from preeclamptic patients, where its levels are correlated with severity of the disease. Overexpression of sEng and sVEGFR-1 in pregnant rodents leads to the development of clinical signs of PE, especially the HELLP syndrom and Intra-Uterine Growth Restriction (IUGR). Classical histological lesions can also be observed in these rodents, as renal endotheliosis, infarcts in placenta or liver...

Our works on explants of first trimester placental villi and on sera and placenta from preeclamptic patients evidence the placental origin of sVEGFR-1. We underline the role of hypoxia in the massive secretion of sVEGFR-1 during PE, by alternative splicing. We suggest a mechanism different from hypoxia and alternative splicing for the production of sEng by preeclamptic patients. Thanks to several in vitro, in vivo and ex vivo models, we decrypt the role of soluble receptors of VEGF (sVEGFRs) in angiogenesis and particularly in vascular maturation, by the recruitment of mural cells. We have also studied the signaling pathways involved in these effects of sVEGFRs. In addition to trapping VEGF at a circulating level, sVEGFR-1 and -2 could form a signaling-inactive membrane-associated complex consisting of sVEGFR/VEGF/ VEGFR-2, both ending to prevent VEGF-driven angiogenesis. They could also bind ECs through interaction with a co-receptor that engaged a PKC-dependent trans-signaling up-regulating S1P1 expression and thus favoring eNOS activation through the S1P/S1P1 pathway. Intracrine VEGF-associated signaling could up-regulate S1P1 expression through a PKC-dependent pathway, thus favoring eNOS activation through the S1P/S1P1 pathway and/or could directly promote eNOS phosphorylation. The subsequent NO release induced the migration of neighbor PC/SMCs, thus promoting mural cells recruitment. We have also studied the way of production of these soluble receptors by endothelial cells. We have shown that hypoxia and inflammation act together to induce the secretion of these factors, by alternative splicing or by proteolysis, in a PKC-dependent pathway.

At the end of this work, PE is still a complex pathology. Our results contribute to clarify some aspects of its physiopathology. We reconcile the vascular and the inflammatory theories, underlining their complementarity. Indeed, it seems that none of them alone can explain the development of PE and others factors could be involved. In the field of our research, we propose to use the algorithm for the prediction of PE to be able to determine risk population to test treatment sibling inflammation or angiogenesis. This would allow closer surveillance and may lead to prophylactic approaches that will require targeted therapies. The ability to prolong pregnancy safely with these therapies even for a short period of time potentially could make a significant improvement in morbidity.

 


 
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