Wang Yidong, Wu Bingruo, Lu Pengfei, Zhang Donghong, Wu Brian, Varshney Shweta, Del Monte-Nieto Gonzalo, Zhuang Zhenwu, Charafeddine Rabab, Kramer Adam H, Sibinga Nicolas E, Frangogiannis Nikolaos G, Kitsis Richard N, Adams Ralf H, Alitalo Kari, Sharp David J, Harvey Richard P, Stanley Pamela, Zhou Bin
Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Nat Commun. 2017 Sep 18;8(1):578. doi: 10.1038/s41467-017-00654-w.
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.Though coronary arteries are crucial for heart function, the mechanisms guiding their formation are largely unknown. Here, Wang et al. identify a unique, endocardially-derived angiogenic precursor cell population for coronary artery formation in mice and show that a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis is key for coronary artery development.
冠状动脉异常可能导致危及生命的心脏并发症；然而，冠状动脉形成的发育机制仍不明确。在这里，我们确定了小鼠冠状动脉形成过程中的一群血管生成细胞。受DLL4/NOTCH1/VEGFA/VEGFR2信号轴调控，这些血管生成细胞生成成熟的冠状动脉。NOTCH调节剂POFUT1对该信号轴起关键调节作用。POFUT1失活会破坏信号事件，导致血管生成细胞过度增殖和血管丛形成，进而导致冠状动脉异常、心肌梗死和心力衰竭。同时失活VEGFR2可完全挽救这些缺陷。这些发现表明，血管生成前体细胞失调将冠状动脉异常与缺血性心脏病联系起来。尽管冠状动脉对心脏功能至关重要，但其形成机制在很大程度上尚不清楚。在这里，王等人确定了小鼠冠状动脉形成过程中一种独特的、源自心内膜的血管生成前体细胞群，并表明DLL4/NOTCH1/VEGFA/VEGFR2信号轴是冠状动脉发育的关键。
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