Tetrahydrobiopterin Prevents Coronary Artery Malformations Induced by Pregestational Diabetes
Notice bibliographique
Résumé
The heart is the first functional organ to form during embryogenesis. Coronary artery development in the heart begins at embryonic day (E)9.5 and involves coordinated epithelial to mesenchymal transition (EMT) and cell differentiation, which form a complete coronary artery network by E15 in the mouse. Alterations in angiogenic gene expression, cell migration or proliferation can have implications on vasculature and heart function, as seen during diabetic embryopathy. Hyperglycemia‐induced oxidative stress can lead to the inactivation of endothelial nitric oxide synthase (eNOS), vital for heart development. Tetrahydrobiopterin (BH4), an antioxidant, is the co‐factor for eNOS, and when oxidized leads to eNOS deactivation, further increasing the oxidative environment. Treatment with BH4 has been shown to improve vascular endothelial function in diabetes. This study aims to investigate the effect of BH4 on embryonic coronary artery development during pregestational maternal diabetes. Diabetes was induced by streptozotocin (STZ, 50 mg/kg, IPx5) to adult female C57BL/6 mice. BH4 (10 mg/kg/day) was orally administered to pregnant mice. Fetal hearts were collected at E18.5 for coronary artery analysis and 3D reconstruction. Markers of EMT and oxidative stress were examined at E12.5 via immunostaining and qPCR. Immunoblotting was used to determine activity of Akt and eNOS. Marked decreases in coronary artery diameter of both the left and right main branches for the coronary tree were found in hearts from diabetic mothers, which were prevented with BH4 administration. Coronary artery abundance and volume were also decreased in diabetic hearts, and recovered to normal levels with BH4 treatment. A normal branching pattern of the vessels was abolished in hearts from diabetic mothers, and returned to normal with BH4. Notably, BH4 treatment to diabetic dams significantly decreased the incidence of CAMs in their offspring from 47.4 to 23.3%. The expression of molecular regulators of angiogenesis such as Snail1 , β‐Catenin , bFGF , Aldh1a2 were decreased with maternal diabetes and reestablished with BH4 supplementation. Additionally, more cell to cell connections, measured through E‐cadherin expression, were found in diabetic hearts and returned to control levels with BH4. The epicardium of hearts from diabetic dams exhibited decreased proliferation and expression of WT1, which were both normalized with BH4 treatment. Furthermore, Akt and eNOS activity, assessed through phosphorylation of both enzymes, was reduced in embryonic hearts from diabetic dams, and was returned to basal levels with BH4 treatment. Finally, oxidative stress, in the form of lipid peroxidation was significantly increased in diabetic hearts and reduced with BH4. BH4 treatment prevents CAMs induced by pregestational diabetes. The importance of BH4‐mediated increase in Akt/eNOS activity and reduction in oxidative stress during cardiac angiogenesis provides insight into factors contributing to CAMs. The therapeutic potential of BH4 during gestation can be extrapolated through these studies. Support or Funding Information This study was funding in parts by grants from the Canadian Institutes of Health Research (CIHR) to Q.F. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».