Format

Send to

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

FGF-dependent metabolic control of vascular development.

Author information

1
Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, USA.
2
Angiogenesis & Metabolism Laboratory, Max Plank Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
3
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine.
4
Department of Cellular and Molecular Physiology, Yale University School of Medicine.
5
Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE, Cambridge, MA, USA.
6
Switch Laboratory, VIB-KU Leuven, Leuven, B-3000, Belgium.
7
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
9
Genomics Laboratory, WuXi NextCODE, Shanghai, China.
10
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago.
11
Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.
12
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, B-3000, Belgium.
13
U970, Paris Cardiovascular Research Center, 56 Rue Leblanc, 75015 Paris, France.
14
Department of Cell Biology, Yale University School of Medicine, New Haven, CT.
#
Contributed equally

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.

PMID:
28467822
PMCID:
PMC5427179
DOI:
10.1038/nature22322
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center