Cell News 01/2017
18
AWARD WINNERS
FOXO1 couples metabolic activity and growth state in the
vascular endothelium
Kerstin Wilhelm
1
, Katharina Happel
1
, Guy Eelen
2,3
, Sandra Schoors
2,3
, Mark F. Oellerich
1
,
Radiance Lim
1
, Barbara Zimmermann
1
, Irene M. Aspalter
4
, Claudio A. Franco
5
,
Thomas Boettger
6
, Thomas Braun6, Marcus Fruttiger
7
, Klaus Rajewsky
8
, Charles Keller
9
,
Jens C. Brüning
10
, Holger Gerhardt
4,8,11,12,13
, Peter Carmeliet
2,3
& Michael Potente
1,14,15
1
Angiogenesis & Metabolism Laboratory, Max Planck Institute for
Heart and Lung Research, D-61231 Bad Nauheim, Germany.
2
Laboratory of Angiogenesis and Neurovascular Link, Vesalius
Research Center, Department of Oncology, University of Leuven,
Leuven 3000, Belgium.
3
Laboratory of Angiogenesis and Neurovascular Link, Vesalius
Research Center, VIB, Leuven 3000, Belgium.
4
Vascular Biology Laboratory, London Research Institute, Cancer
Research UK, London WC2A 3LY, UK. 5Vascular Morphogene-
sis Laboratory, Instituto de Medicina Molecular, Faculdade de
Medicina da Universidade de Lisboa, Lisbon 1649-028, Portugal.
6
Department of Cardiac Development and Remodeling, Max
Planck Institute for Heart and Lung Research, D-61231 Bad
Nauheim, Germany.
7
UCL Institute of Ophthalmology, University College London,
London EC1V 9EL, UK.
8
Max Delbrück Center for Molecular Medicine (MDC), D-13125
Berlin, Germany.
9
Children’s Cancer Therapy Development Institute, Beaverton,
Oregon 97005, USA.
10
Max Planck Institute for Metabolism Research, Excellence Clus-
ter on Cellular Stress Responses in Aging- Associated Diseases
(CECAD) and Center of Molecular Medicine Cologne (CMMC),
Center for Endocrinology, Diabetes and Preventive Medicine
(CEDP), University of Cologne, D-50931 Cologne, Germany.
11
Vascular Patterning Laboratory, Vesalius Research Center, VIB
and University of Leuven, Leuven 3000, Belgium.
12
DZHK (German Center for Cardiovascular Research), partner site
Berlin, D-13347 Berlin, Germany. 13Berlin Institute of Health
(BIH), D-10117 Berlin, Germany.
14
International Institute of Molecular and Cell Biology, 02-109
Warsaw, Poland.
15
DZHK (German Center for Cardiovascular Research), partner site
Frankfurt Rhine-Main, D-13347 Berlin, Germany.
Endothelial cells (ECs) are plastic cells that can switch between
growth states with different bioenergetic and biosynthetic
requirements1. Although quiescent in most healthy tissues, ECs
divide and migrate rapidly upon proangiogenic stimulation2,3.
Adjusting endothelial metabolism to the growth state is central
to normal vessel growth and function1,4, yet it is poorly under-
stood at the molecular level. Here we report that the forkhead
box O (FOXO) transcription factor FOXO1 is an essential regu-
lator of vascular growth that couples metabolic and prolifera-
tive activities in ECs. Endothelial-restricted deletion of FOXO1
in mice induces a profound increase in EC proliferation that
interferes with coordinated sprouting, thereby causing hyper-
plasia and vessel enlargement. Conversely, forced expression of
FOXO1 restricts vascular expansion and leads to vessel thinning
and hypobranching. We find that FOXO1 acts as a gatekeeper
of endothelial quiescence, which decelerates metabolic activity
by reducing glycolysis and mitochondrial respiration. Mech-
anistically, FOXO1 suppresses signalling by MYC (also known
as c-MYC), a powerful driver of anabolic metabolism and
growth5,6. MYC ablation impairs glycolysis, mitochondrial func-
tion and proliferation of ECs while its EC-specific overexpression
fuels these processes. Moreover, restoration of MYC signalling
in FOXO1-overexpressing endothelium normalizes metabolic
activity and branching behaviour. Our findings identify FOXO1 as
a critical rheostat of vascular expansion and define the FOXO1–
MYC transcriptional network as a novel metabolic checkpoint
during endothelial growth and proliferation.
1. Ghesquière, B., Wong, B. W., Kuchnio, A. & Carmeliet, P.
Metabolism of stromal and immune cells in health and
disease. Nature 511, 167–176 (2014).
2. Adams, R. H. & Alitalo, K. Molecular regulation of angio-
genesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8,
464–478 (2007).
3. Potente, M., Gerhardt, H. & Carmeliet, P. Basic and thera-
peutic aspects of angiogenesis. Cell 146, 873–887 (2011).
4. De Bock, K., Georgiadou, M. & Carmeliet, P. Role of Endo-
thelial Cell Metabolism in Vessel Sprouting. Cell Metab. 18,
634–647 (2013).
5. Dang, C. V. MYC, metabolism, cell growth, and tumorigenesis.
Cold Spring Harb Perspect Med 3, a014217–a014217 (2013).
6. Adhikary, S. & Eilers, M. Transcriptional regulation and trans-
formation by Myc proteins. Nat. Rev. Mol. Cell Biol. 6,
635–645 (2005).
