Journal Article

FGF-dependent metabolic control of vascular development

Tung, Joe K., Hay, Nissim, Yu, Pengchun, De Smet, Frederik, Alves, Tiago C., Chen, Zehua, Sun, Hongye, Jin, Suk-Won, Kibbey, Richard G., Eichmann, Anne, Xie, Yi, Dubrac, Alexandre, Sun, Lele, Simons, Michael, Hirschi, Karen K., Potente, Michael, Wilhelm, Kerstin, Chittenden, Thomas W., Carmeliet, Peter, Fang, Jennifer S., Zhang, Jiasheng, Zhu, Jie

2017

Overview

Fibroblast growth factor receptor (FGFR) signalling is a crucial regulator of endothelial metabolism and vascular development. The role of fibroblasts in vascular development The development of blood vessel networks involves the growth and spread of endothelial cells. Recent studies suggest that these processes are affected by changes in cellular metabolism, but the role of fibroblast growth factors (FGFs) is poorly understood. Michael Simons and colleagues identify FGF receptor signalling as a crucial regulator of vascular development andendothelial cell proliferation in adult tissues. They explore the molecular basis of this effect and find that FGFs control endothelial cell glycolysis through MYC-dependent regulation of hexokinase 2 expression. The authors suggest that understanding this pathway may guide investigations into targeted therapies for diseases associated with irregular vascular growth. 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 1 . Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism 2 , 3 , little is understood about the role of fibroblast growth factors (FGFs) in this context 4 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/290 / 631/80/86/2368 / Angiogenesis / Animals / Biology / Blood / c-Myc protein / Cell growth / Cell Movement / Cell Proliferation / Defects / Endothelial cells / Endothelial Cells - cytology / Endothelial Cells - metabolism / Endothelium / Enzymes / Female / Fibroblast growth factor receptor 1 / Fibroblast growth factor receptors / Fibroblast growth factors / Fibroblast Growth Factors - metabolism / Glycolysis / Grants / Growth factors / Health aspects / Hexokinase / Hexokinase - metabolism / Homeostasis / Humanities and Social Sciences / Kinases / letter / Lymphangiogenesis / Lymphatic Vessels - cytology / Lymphatic Vessels - metabolism / Medical research / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / multidisciplinary / Myc protein / Neovascularization, Physiologic / Observations / Oxygenation / Proto-Oncogene Proteins c-myc - metabolism / Receptor, Fibroblast Growth Factor, Type 1 - deficiency / Receptor, Fibroblast Growth Factor, Type 1 - genetics / Receptor, Fibroblast Growth Factor, Type 1 - metabolism / Receptor, Fibroblast Growth Factor, Type 3 - deficiency / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Rodents / Science / Signal Transduction / Vascular endothelial growth factor