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 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 and Bin Zhou ()
Additional contact information
Yidong Wang: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Bingruo Wu: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Pengfei Lu: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Donghong Zhang: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Brian Wu: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Shweta Varshney: Albert Einstein College of Medicine
Gonzalo Monte-Nieto: Victor Chang Cardiac Research Institute
Zhenwu Zhuang: Yale University
Rabab Charafeddine: Albert Einstein College of Medicine
Adam H. Kramer: Albert Einstein College of Medicine
Nicolas E. Sibinga: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Nikolaos G. Frangogiannis: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Richard N. Kitsis: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine
Ralf H. Adams: Max-Planck-Institute for Molecular Biomedicine
Kari Alitalo: Wihuri Research Institute, Biomedicum Helsinki
David J. Sharp: Albert Einstein College of Medicine
Richard P. Harvey: Victor Chang Cardiac Research Institute
Pamela Stanley: Albert Einstein College of Medicine
Bin Zhou: Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00654-w

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