Universität zu Köln

Wilhelm, Kerstin, Happel, Katharina, Eelen, Guy, Schoors, Sandra, Oellerich, Mark F., Lim, Radiance ORCID: 0000-0002-9865-7064, Zimmermann, Barbara, Aspalter, Irene M., Franco, Claudio A., Boettger, Thomas ORCID: 0000-0003-4280-8449, Braun, Thomas ORCID: 0000-0002-6165-4804, Fruttiger, Marcus ORCID: 0000-0002-6962-5485, Rajewsky, Klaus ORCID: 0000-0002-6633-6370, Keller, Charles, Bruening, Jens C., Gerhardt, Holger ORCID: 0000-0002-3030-0384, Carmeliet, Peter ORCID: 0000-0001-7961-1821 and Potente, Michael ORCID: 0000-0002-5689-0036 (2016). FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature, 529 (7585). S. 216 - 234. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements(1). Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation(2,3). Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function(1,4), yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia 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. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c-MYC), a powerful driver of anabolic metabolism and growth(5,6). MYC ablation impairs glycolysis, mitochondrial function 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wilhelm, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Happel, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Eelen, Guy UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoors, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Oellerich, Mark F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Radiance UNSPECIFIED orcid.org/0000-0002-9865-7064 UNSPECIFIED Zimmermann, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Aspalter, Irene M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Franco, Claudio A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettger, Thomas UNSPECIFIED orcid.org/0000-0003-4280-8449 UNSPECIFIED Braun, Thomas UNSPECIFIED orcid.org/0000-0002-6165-4804 UNSPECIFIED Fruttiger, Marcus UNSPECIFIED orcid.org/0000-0002-6962-5485 UNSPECIFIED Rajewsky, Klaus UNSPECIFIED orcid.org/0000-0002-6633-6370 UNSPECIFIED Keller, Charles UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerhardt, Holger UNSPECIFIED orcid.org/0000-0002-3030-0384 UNSPECIFIED Carmeliet, Peter UNSPECIFIED orcid.org/0000-0001-7961-1821 UNSPECIFIED Potente, Michael UNSPECIFIED orcid.org/0000-0002-5689-0036 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-287294
DOI:	10.1038/nature16498
Journal or Publication Title:	Nature
Volume:	529
Number:	7585
Page Range:	S. 216 - 234
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSCRIPTION FACTOR; GENE-EXPRESSION; MYC; IDENTIFICATION; ANGIOGENESIS; CELLS; MICE; MAINTENANCE; HOMEOSTASIS; INSULIN Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28729