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Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections.

ABSTRACT: Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is thought to be minor and nonsignificant for coronary formation. Using classic (Wt1(Cre)) and previously undescribed (G2-Gata4(Cre)) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/proepicardium (ST/PE)-derived endothelial cells are required for the formation of ventricular coronary arterio-venous vascular connections. Our results indicate that at least 20% of embryonic coronary arterial and capillary endothelial cells derive from the ST/PE compartment. Moreover, we show that conditional deletion of the ST/PE lineage-specific Wilms' tumor suppressor gene (Wt1) in the ST/PE of G2-Gata4(Cre) mice and in the endothelium of Tie2(Cre) mice disrupts embryonic coronary transmural patterning, leading to embryonic death. Taken together, our results demonstrate that ST/PE-derived endothelial cells contribute significantly to and are required for proper coronary vascular morphogenesis.

SUBMITTER: Cano E

PROVIDER: S-EPMC4725486 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections.

Cano Elena E Carmona Rita R Ruiz-Villalba Adrián A Rojas Anabel A Chau You-Ying YY Wagner Kay D KD Wagner Nicole N Hastie Nicholas D ND Muñoz-Chápuli Ramón R Pérez-Pomares José M JM

Proceedings of the National Academy of Sciences of the United States of America 20160106 3

Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is thought to be minor and nonsignificant for coronary formation. Using classic (Wt1(Cre)) and previously undescribed (G2-Gata4(Cre)) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/proepicardium (ST/PE)-derived endothelial cells are requ ...[more]

PMID: 26739565

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Project description:Objectives: We have previously identified a population of cells that expressed stemness-associated markers in extracranial arterio-venous malformation (AVM) and demonstrated expression of cathepsins B, D, and G on embryonic stem cell (ESC)-like populations in other vascular anomalies. This study investigated the expression of cathepsins B, D, and G, and their localization in relation to this primitive population in extracranial AVM. Methods: Immunohistochemical staining was performed on AVM tissue samples from 13 patients to demonstrate expression of cathepsins B, D, and G. Western blotting was performed on four AVM tissue samples and three AVM-derived primary cell lines to confirm protein expression of cathepsins B and D proteins. RT-qPCR was performed on three AVM-derived primary cell lines to demonstrate transcript expression of cathepsins B, D, and G. Enzymatic activity assays were performed on three AVM-derived primary cell lines to investigate if cathepsins B and D were active. Localization of the cathepsins was investigated using immunofluorescence dual-staining of the cathepsins with the ESC markers OCT4 and SOX2, and mast cells marker chymase on two of the 13 AVM tissue samples. Results: Immunohistochemical staining demonstrated expression of cathepsins B, D, and G in all 13 AVM tissue samples. Western blotting showed expression of cathepsins B and D proteins in all four AVM tissue samples and all three AVM-derived primary cell lines. RT-qPCR demonstrated transcripts of cathepsins B, D, and G in all three AVM-derived primary cell lines. Enzymatic activity assays showed that cathepsins B and D were active. Immunofluorescence staining showed expression of cathepsins B and D on the OCT4+/SOX2+ endothelium and media of the lesional vessels and cells within the stroma in AVM nidus. Cathepsin G was expressed on the chymase+ phenotypic mast cells. Conclusions: This study demonstrated the novel finding of the expression of cathepsins B, D, and G in AVM. Cathepsins B and D were expressed by the primitive population, and cathepsin G was localized to mast cells, within the AVM nidus.

Project description:ObjectivesTo compare the detection of relevant extracardiac findings (ECFs) on coronary computed tomography angiography (CTA) and invasive coronary angiography (ICA) and evaluate the potential clinical benefit of their detection.MethodsThis is the prespecified subanalysis of ECFs in patients presenting with a clinical indication for ICA based on atypical angina and suspected coronary artery disease (CAD) included in the prospective single-center randomized controlled Coronary Artery Disease Management (CAD-Man) study. ECFs requiring immediate therapy and/or further workup including additional imaging were defined as clinically relevant. We evaluated the scope of ECFs in 329 patients and analyzed the potential clinical benefit of their detection.ResultsECFs were detected in 107 of 329 patients (32.5%; CTA: 101/167, 60.5%; ICA: 6/162, 3.7%; p < .001). Fifty-nine patients had clinically relevant ECFs (17.9%; CTA: 55/167, 32.9%; ICA: 4/162, 2.5%; p < .001). In the CTA group, ECFs potentially explained atypical chest pain in 13 of 101 patients with ECFs (12.9%). After initiation of therapy, chest pain improved in 4 (4.0%) and resolved in 7 patients (6.9%). Follow-up imaging was recommended in 33 (10.0%; CTA: 30/167, 18.0%; ICA: 3/162, 1.9%) and additional clinic consultation in 26 patients (7.9%; CTA: 25/167, 15.0%; ICA: 1/162, 0.6%). Malignancy was newly diagnosed in one patient (0.3%; CTA: 1/167, 0.6%; ICA: 0).ConclusionsIn this randomized study, CTA but not ICA detected clinically relevant ECFs that may point to possible other causes of chest pain in patients without CAD. Thus, CTA might preclude the need for ICA in those patients.Trial registrationNCT Unique ID: 00844220 KEY POINTS: • CTA detects ten times more clinically relevant ECFs than ICA. • Actionable clinically relevant ECFs affect patient management and therapy and may thus improve chest pain. • Detection of ECFs explaining chest pain on CTA might preclude the need for performing ICA.

Dataset Information

Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections.

Publications

Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections.

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