Abstract
The coronary vasculature is crucial for normal heart function, yet much remains to be learned about its development, especially the maturation of coronary arterial endothelium. Here, we show that endothelial inactivation of ADAM10, a key regulator of Notch signaling, leads to defects in coronary arterial differentiation, as evidenced by dysregulated genes related to Notch signaling and arterial identity. Moreover, transcriptome analysis indicated reduced EGFR signaling in A10ΔEC coronary endothelium. Further analysis revealed that A10ΔEC mice have enlarged dysfunctional hearts with abnormal myocardial compaction, and increased expression of venous and immature endothelium markers. These findings provide the first evidence for a potential role for endothelial ADAM10 in cardioprotective homeostatic EGFR signaling and implicate ADAM10/Notch signaling in coronary arterial cell specification, which is vital for normal heart development and function. The ADAM10/Notch signaling pathway thus emerges as a potential therapeutic target for improving the regenerative capacity and maturation of the coronary vasculature.
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Acknowledgements
We thank the Weill Cornell Genomics core for their contribution to the RNA-seq analysis presented here. In addition, we would like to thank Chad Kurylo for his insightful comments and suggestions. This study was funded in part by NIH GM64750 to CPB. G. Farber is funded by American Heart Association Predoctoral Fellowship (#17PRE33380001). S. Monette and the Laboratory of Comparative Pathology was supported in part by NCI Grant P30 CA008748. A. di Lorenzo was supported by NIH NHLBI R01HL126913 and NINDS R21NS104512.
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GF and CB designed the experiments and prepared the manuscript. GF harvested all tissue and maintained the mouse colony. GF performed immunofluorescence experiments and analyses. MP performed the RNA-seq analysis. GF and NLG prepared the samples for RNA sequencing. YZ performed the echocardiogram experiments. SM analyzed and collected images for histopathology analysis. AdL and SB provided resources and relevant feedback. All authors contributed to the editing of the manuscript.
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Farber, G., Parks, M.M., Lustgarten Guahmich, N. et al. ADAM10 controls the differentiation of the coronary arterial endothelium. Angiogenesis 22, 237–250 (2019). https://doi.org/10.1007/s10456-018-9653-2
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DOI: https://doi.org/10.1007/s10456-018-9653-2