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Title: Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature
Authors: Aranguren, Xabier L ×
Agirre, Xabier
Beerens, Manu
Coppiello, Giulia
Uriz, Maialen
Vandersmissen, Ine
Benkheil, Mohammed
Panadero, Joaquin
Aguado, Natalia
Pascual-Montano, Alberto
Segura, Victor
Prósper, Felipe
Luttun, Aernout #
Issue Date: Dec-2013
Publisher: W.B. Saunders
Series Title: Blood vol:122 issue:24 pages:3982-92
Article number: 10.1182/blood-2013-02-483255
Abstract: Endothelial cells (ECs) lining arteries and veins have distinct molecular/functional signatures. The underlying regulatory mechanisms are incompletely understood. Here, we established a specific fingerprint of freshly isolated arterial and venous ECs from human umbilical cord comprising 64 arterial and 12 venous genes, representing distinct functions/pathways. Among the arterial genes were 8 transcription factors (TFs), including Notch target HEY2, the current "gold standard" determinant for arterial EC (aEC) specification. Culture abrogated differential gene expression in part due to gradual loss of canonical Notch activity and HEY2 expression. Notably, restoring HEY2 expression or Delta-like4-induced Notch signaling in cultured ECs only partially reinstated the aEC gene signature, whereas combined overexpression of the 8 TFs restored this fingerprint more robustly. Whereas some TFs stimulated few genes, others boosted a large proportion of arterial genes. Although there was some overlap and cross-regulation, the TFs largely complemented each other in regulating the aEC gene profile. Finally, overexpression of the 8 TFs in human umbilical vein ECs conveyed an arterial-like behavior upon their implantation in a Matrigel plug in vivo. Thus, our study shows that Notch signaling determines only part of the aEC signature and identifies additional novel and complementary transcriptional players in the complex regulation of human arteriovenous EC identity.
URI: 
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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