RÉSUMÉ
Coordinated arterial-venous differentiation is crucial for vascular development and function. The origin of the cardinal vein (CV) in mammals is unknown, while conflicting theories have been reported in chick and zebrafish. Here, we provide the first molecular characterization of endothelial cells (ECs) expressing venous molecular markers, or venous-fated ECs, within the emergent dorsal aorta (DA). These ECs, expressing the venous molecular markers Coup-TFII and EphB4, cohabited the early DA with ECs expressing the arterial molecular markers ephrin B2, Notch and connexin 40. These mixed ECs in the early DA expressed either the arterial or venous molecular marker, but rarely both. Subsequently, the DA exhibited uniform arterial markers. Real-time imaging of mouse embryos revealed EC movement from the DA to the CV during the stage when venous-fated ECs occupied the DA. We analyzed mutants for EphB4, which encodes a receptor tyrosine kinase for the ephrin B2 ligand, as we hypothesized that ephrin B2/EphB4 signaling may mediate the repulsion of venous-fated ECs from the DA to the CV. Using an EC quantification approach, we discovered that venous-fated ECs increased in the DA and decreased in the CV in the mutants, whereas the rest of the ECs in each vessel were unaffected. This result suggests that the venous-fated ECs were retained in the DA and missing in the CV in the EphB4 mutant, and thus that ephrin B2/EphB4 signaling normally functions to clear venous-fated ECs from the DA to the CV by cell repulsion. Therefore, our cellular and molecular evidence suggests that the DA harbors venous progenitors that move to participate in CV formation, and that ephrin B2/EphB4 signaling regulates this aortic contribution to the mammalian CV.
Sujet(s)
Aorte/cytologie , Cellules souches/cytologie , Veines/cytologie , Animaux , Cellules endothéliales/cytologie , Cellules endothéliales/métabolisme , Souris , Souris transgéniques , Néovascularisation physiologique/physiologie , Transduction du signal/physiologie , Cellules souches/métabolismeRÉSUMÉ
BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with significant neonatal morbidity and mortality. Although prenatal complete tracheal occlusion (cTO) causes hypoplastic CDH lungs to enlarge, improved lung function has not been demonstrated. Furthermore, cTO interferes with the dynamic pressure change and fluid flow associated with fetal breathing. PURPOSE: The purpose of the study was to assess a novel dynamic tracheal occlusion (dTO) device that preserves pressure changes and fluid flow. METHODS: In this pilot study, CDH was created in fetal lambs at 65 days of gestational age (GA). At 110 days GA, a cTO device (n = 3) or a dTO device (n = 4) was placed in the fetal trachea. At 135 days GA, lambs were delivered and resuscitated. Unoperated lamb co-twins (n = 5), sham thoracotomy lambs (n = 2), and untreated CDH lambs (n = 3) served as controls. RESULTS: Tracheal opening pressure, lung volume, lung fluid total protein, and phospholipid were significantly higher in the cTO group than in the dTO and unoperated control groups. Maximal oxygenation and lung compliance were significantly lower in the cTO group when compared with the unoperated control and dTO groups. CONCLUSION: Preliminary results suggest that in the fetal lamb CDH model, dTO restores normal lung morphometrics and function, whereas cTO leads to enlarged but less functional lungs.
Sujet(s)
Endoscopie/méthodes , Maladies foetales/chirurgie , Hernies diaphragmatiques congénitales , Hypertension pulmonaire/prévention et contrôle , Implants expérimentaux , Poumon/embryologie , Trachée/chirurgie , Analyse de variance , Animaux , Animaux nouveau-nés , Modèles animaux de maladie humaine , Endoscopes , Conception d'appareillage , Sécurité du matériel , Femelle , Hernie diaphragmatique/complications , Hernie diaphragmatique/chirurgie , Hypertension pulmonaire/étiologie , Poumon/croissance et développement , Projets pilotes , Grossesse , Gestation animale , Répartition aléatoire , Tests de la fonction respiratoire , Facteurs de risque , Sensibilité et spécificité , OvisRÉSUMÉ
OBJECTIVE: To examine the outcomes of patients with twin reversed arterial perfusion (TRAP) sequence in which the acardiac twin was Sujet(s)
Ablation par cathéter
, Maladies chez les jumeaux/thérapie
, Coeur foetal/malformations
, Cardiopathies congénitales/thérapie
, Maladies chez les jumeaux/physiopathologie
, Femelle
, Cardiopathies congénitales/anatomopathologie
, Humains
, Grossesse
, Issue de la grossesse
, Études rétrospectives
, Résultat thérapeutique
RÉSUMÉ
A mutual coordination of size between developing arteries and veins is essential for establishing proper connections between these vessels and, ultimately, a functional vasculature; however, the cellular and molecular regulation of this parity is not understood. Here, we demonstrate that the size of the developing dorsal aorta and cardinal vein is reciprocally balanced. Mouse embryos carrying gain-of-function Notch alleles show enlarged aortae and underdeveloped cardinal veins, whereas those with loss-of-function mutations show small aortae and large cardinal veins. Notch does not affect the overall number of endothelial cells but balances the proportion of arterial to venous endothelial cells, thereby modulating the relative sizes of both vessel types. Loss of ephrin B2 or its receptor EphB4 also leads to enlarged aortae and underdeveloped cardinal veins; however, endothelial cells with venous identity are mislocalized in the aorta, suggesting that ephrin B2/EphB4 signaling functions distinctly from Notch by sorting arterial and venous endothelial cells into their respective vessels. Our findings provide mechanistic insight into the processes underlying artery and vein size equilibration during angiogenesis.