Role of Retinoic Acid Signaling in Epicardial‐Related Events During Late Heart Development
Bibliographic record
Abstract
Background During the final stages of heart development, the myocardium grows and becomes vascularized with the aid of paracrine factors and cell progenitors derived from the epicardium. Here, we study the involvement of retinoic acid (RA), a metabolite of vitamin A, in epicardial‐related developmental processes involving the formation of the coronary vasculature and the growth of the ventricular compact zone. Methods To explore the developmental consequences of altered RA signaling in late cardiogenic events, we employed a previously characterized model of embryonic RA excess based on mouse embryos deficient in the retinaldehyde reductase DHRS3. We also employed a complementary model based on embryonic RA deficiency generated by administering WIN 18,446, a bis(dichloroacetyl)diamine inhibitor of RA synthesis to pregnant dams. Using these two models we studied the formation of the coronary plexus and the formation and recruitment of epicardial‐derived mural cells by coronary vessels. We further explored the effect of altered RA in vitro by studying the epicardial epithelial‐to‐mesenchymal transition (EMT), and the formation, migration and differentiation of epicardial‐derived precursor cells (EPDCs). Results Our results demonstrated that both excess and deficiency of embryonic RA‐signaling led to a thin ventricular myocardium and aberrant coronary vessel formation and remodeling. In the case of both excess, or deficient RA‐signaling, the endothelial tubes did not become invested with epicardial‐derived vascular smooth muscle cells (VSMCs). In vitro assays of epicardial EMT combined with transcriptomic and proteomic analyses revealed that RA signaling not only affects the differentiation of EPDCs, but also controls the cytoskeletal reorganization and secretion of angiogenic and cardiotrophic factors by the epicardium. Conclusion We report that RA signaling affects epicardial signaling and plays critical roles in the development of the myocardium and the coronary vasculature. Support or Funding Information This work was supported in part by the grant R01HD077260 (ARM, MAK) from the National Institutes of Health and by a Fulbright U.S. Scholar Award to ARM funded by the U.S. Department of State's Bureau of Educational and Cultural Affairs, the Commission for Educational Exchange between the United States of America and Brazil and CAPES, the Brazilian Federal Agency for Support and Evaluation of Graduate Education. Additional support to MAK was provided by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841‐IQB2014) and by startup funds to ARM from the Northern Ontario School of Medicine. Conflicts of interest: none.
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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 | 0.001 |
| 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".