Mechanisms in Endovascular Differentiation of the Trophoblast and Its Regulation by Decorin.
Notice bibliographique
Résumé
Introduction: Extravillous trophoblast (EVT) cells of the human placenta invade the uterine decidua and modify the utero-placental arteries in order to establish an efficient exchange of key molecules between the maternal and fetal blood. During invasion of the arteries EVT cells adopt an endothelial phenotype (endovascular differentiation) to replace arterial endothelium. EVT invasion is stringently regulated in-situ both positively and negatively by a variety of factors at the fetal-maternal interface to maintain a healthy utero-placental homeostasis. A break down in this homeostasis can occur in hypo-invasive trophoblast disorders such as maternal preeclampsia and fetal growth restriction; or in hyper-invasive trophoblast disorders such as placenta accreta/ percreta and trophoblastic neoplasias. We found that decidua-derived VEGF promotes EVT proliferation and migration, whereas two other decidua derived factors TGF-β and a TGF-β binding leucine-rich proteoglycan decorin (DCN) inhibit EVT proliferation, migration and invasiveness independent of each other. We reported that these decorin actions are differentially mediated by its binding to multiple tyrosine kinase receptors including EGF-R, IGF-R1 and VEGF receptor (VEGFR)-2 expressed by the EVT. VEGFR-2 binding site in DCN was localized to its leucine-rich-repeat (LLR)-5 domain. However, mechanisms underlying endovascular differentiation of the EVT and its possible regulation by DCN remain unclear. Objectives and approaches: Present study utilized the first trimester human EVT cell line, HTR-8/SVneo (1) To test whether VEGF promoted endovascular differentiation of the EVT, and if so, (2) To identify molecular mechanisms underlying decorin antagonism of VEGF–mediated EVT cell migration and endovascular differentiation. The latter was measured by the ability of the EVT (a) to form endothelial-like tubes on matrigel and (b) to express endothelial activation markers VE-cadherin and β-catenin. Results: (1) Exogenous VEGF stimulated migration and endothelial- like tube formation, and upregulated VE-cadherin and β-catenin in EVT cells. Similar upregulation was also noted in endothelial cells. This upregulation was shown to be exclusively VEGFR-2 dependent, since it was prevented by siRNA-mediated knock down of VEGFR-2 in the EVT. (2) DCN was shown to block all of the above VEGF-stimulated events. (3) Exogenous VEGF stimulated phosphorylation of MAPKs (P38 MAPK and ERK1/2) in EVT cells, and the stimulation was blocked in both cases by decorin. Employing selective p38 MAPK and ERK1/2inhibitors, we established that both pathways contributed independently to VEGF-induced EVT migration and tube formation. Finally, VEGF-mediated upregulation of VE-cadherin and β-catenin in the EVT as well as endothelial cells was blocked by both MAPK inhibitors, indicating MAPK dependence. Conclusion: These results reveal that decorin antagonizes VEGF-stimulation of trophoblast migration and endovascular differentiation by interfering with p38 MAPK and ERK1/2 activation. Significance: Decorin mediated dual impediment of endovascular differentiation of the EVT and angiogenesis in the placental bed may have implications for pathogenesis of preeclampsia, a hypo-invasive trophoblast disorder in pregnancy. (Supported by the CIHR grant to PKL.)
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».