title: Genetic lineage tracing discloses arteriogenesis as the main mechanism for collateral growth in the mouse heart.
abstract: OBJECTIVE
  Capillary and arterial endothelial cells share many common molecular markers in both the neonatal and adult hearts. Herein, we aim to establish a genetic tool that distinguishes these two types of vessels in order to determine the cellular mechanism underlying collateral artery formation.
  
  
  RESULTS
  Using Apln-GFP and Apln-LacZ reporter mice, we demonstrate that APLN expression is enriched in coronary vascular endothelial cells. However, APLN expression is reduced in coronary arterial endothelial cells. Genetic lineage tracing, using an Apln-CreER mouse line, robustly labelled capillary endothelial cells, but not arterial endothelial cells. We leveraged this differential activity of Apln-CreER to study collateral artery formation following myocardial infarction (MI). In a neonatal heart MI model, we found that Apln-CreER-labelled capillary endothelial cells do not contribute to the large collateral arteries. Instead, these large collateral arteries mainly arise from pre-existing, infrequently labelled coronary arteries, indicative of arteriogenesis. Furthermore, in an adult heart MI model, Apln-CreER activity also distinguishes large and small diameter arteries from capillaries. Lineage tracing in this setting demonstrated that most large and small coronary arteries in the infarcted myocardium and border region are derived not from capillaries, but from pre-existing arteries.
  
  
  CONCLUSIONS
  Apln-CreER-mediated lineage tracing distinguishes capillaries from large arteries, in both the neonatal and adult hearts. Through genetic fate mapping, we demonstrate that pre-existing arteries, but not capillaries, extensively contribute to collateral artery formation following myocardial injury. These results suggest that arteriogenesis is the major mechanism underlying collateral vessel formation.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: He
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qiaozhen
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Hu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Tian
authors.affiliation: Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Aix Marseille Universite, CNRS, IBDM UMR 7288, Marseille 13288, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.affiliation: Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wythe
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China ShanghaiTech University, Shanghai 201210, China zhoubin@sibs.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003097:Collateral Circulation / Q000235:genetics*; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006321:Heart / Q000254:growth & development*; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics*
keywords: Apln-CreER; Arterialization; Arteriogenesis; Collateral artery; Lineage tracing