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FGF-dependent metabolic control of vascular development

Item Type:Article
Title:FGF-dependent metabolic control of vascular development
Creators Name:Yu, P. and Wilhelm, K. and Dubrac, A. and Tung, J.K. and Alves, T.C. and Fang, J.S. and Xie, Y. and Zhu, Ji. and Chen, Z. and De Smet, F. and Zhang, J. and Jin, S.W. and Sun, L. and Sun, H. and Kibbey, R.G. and Hirschi, K.K. and Hay, N. and Carmeliet, P. and Chittenden, T.W. and Eichmann, A. and Potente, M. and Simons, M.
Abstract:Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.
Keywords:Cell Movement, Cell Proliferation, Endothelial Cells, Fibroblast Growth Factors, Glycolysis, Hexokinase, Inbred C57BL Mice, Lymphangiogenesis, Lymphatic Vessels, Physiologic Neovascularization, Proto-Oncogene Proteins c-myc, Signal Transduction, Type 1 Fibroblast Growth Factor Receptor, Type 3 Fibroblast Growth Factor Receptor, Animals, Mice
Publisher:Nature Publishing Group
Page Range:224-228
Date:11 May 2017
Official Publication:https://doi.org/10.1038/nature22322
PubMed:View item in PubMed

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