Mechanisms in Endovascular Differentiation of the Trophoblast and Its Regulation by Decorin.
Bibliographic record
Abstract
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.)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".