Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1

Yidong Wang, Bingruo Wu, Pengfei Lu, Donghong Zhang, Brian Wu, Shweta Varshney, Gonzalo Del Monte-Nieto, Zhenwu Zhuang, Rabab Charafeddine, Adam H. Kramer, Nicolas E. Sibinga, Nikolaos G. Frangogiannis, Richard N. Kitsis, Ralf H. Adams, Kari Alitalo, David J. Sharp, Richard P. Harvey, Pamela Stanley, Bin Zhou

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Abstract

Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in excessive angiogenic cell proliferation and plexus formation, leading to anomalous coronary arteries, myocardial infarction and heart failure. Simultaneous VEGFR2 inactivation fully rescues these defects. These findings show that dysregulated angiogenic precursors link coronary anomalies to ischemic heart disease.

Original languageEnglish
Article number578
Number of pages15
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 18 Sep 2017
Externally publishedYes

Cite this

Wang, Y., Wu, B., Lu, P., Zhang, D., Wu, B., Varshney, S., Del Monte-Nieto, G., Zhuang, Z., Charafeddine, R., Kramer, A. H., Sibinga, N. E., Frangogiannis, N. G., Kitsis, R. N., Adams, R. H., Alitalo, K., Sharp, D. J., Harvey, R. P., Stanley, P., & Zhou, B. (2017). Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1. Nature Communications, 8(1), [578]. https://doi.org/10.1038/s41467-017-00654-w