FGF-dependent metabolic control of vascular development

Nature. 2017 May 11;545(7653):224-228. doi: 10.1038/nature22322. Epub 2017 May 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism*
  • Female
  • Fibroblast Growth Factors / metabolism*
  • Glycolysis*
  • Hexokinase / metabolism
  • Lymphangiogenesis
  • Lymphatic Vessels / cytology
  • Lymphatic Vessels / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic*
  • 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
  • Signal Transduction*

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Fibroblast Growth Factors
  • Hexokinase
  • hexokinase 2, mouse
  • Fgfr1 protein, mouse
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 3