Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1,2,3,4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1,2,3,4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates β1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both β1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.
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Source Data for all quantifications are provided. Supplementary Video 1 is available at https://figshare.com/s/7f48df3583bff7ce0ea1; Supplementary Video 2 is available at https://figshare.com/s/361947a6f67b8b925042; and Supplementary Video 3 is available at https://figshare.com/s/f7ceb9d5980d10084ad8. Full scans of western blots are provided in Supplementary Fig. 1.
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This work was supported by Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Centres SFB 974 (‘Communication and Systems Relevance during Liver Damage and Regeneration’), SFB 1116 (‘Master switches in cardiac ischemia’), IRTG 1902 (‘Intra- and interorgan communication of the cardiovascular system’) as well as DFG LA1216/6-1 (‘Investigation of the role of vascular endothelium in blood glucose metabolism’), the German Center for Diabetes Research (DZD e.V.), the Federal Ministry of Health, the Ministry of Culture and Science of North Rhine-Westphalia, the Academy of Finland, the Novo Nordisk Foundation and Helsinki Institute of Life Science (HiLIFE). We are also grateful to Y. Koh for schematic illustrations, M. Astrachan and his team (XVIVO scientific animation) for the animation, L. S. Hilger for establishing VEGFR3 western blots, S. Jakob, B. Bartosinska, A. Köster and T. Zobel (Centre for Advanced Imaging) for technical support as well as B.-F. Belgardt, C. Bridges, M. Kelly-Goss and M. Gearing for critical reading of the manuscript.
Nature thanks G. Michalopoulos, E. Tzima and the other anonymous reviewer(s) for their contribution to the peer review of this work.