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Aranguren X.L.,Molecular and Vascular Biology Research Unit | Beerens M.,Molecular and Vascular Biology Research Unit | Coppiello G.,Molecular and Vascular Biology Research Unit | Wiese C.,University of Wurzburg | And 5 more authors.
Journal of Cell Science | Year: 2013

Endothelial cell (EC) identity is in part genetically predetermined. Transcription factor NR2F2 (also known as chicken ovalbumin upstream promoter transcription factor II, COUP-TFII) plays a key role in EC fate decision making; however, many of the underlying mechanisms remain enigmatic. In the present study, we demonstrate that NR2F2 differentially regulates gene expression of venous versus lymphatic ECs (LECs) and document a novel paradigm whereby NR2F2 homodimers induce a venous EC fate, while heterodimers with the LEC-specific transcription factor PROX1 instruct LEC lineage specification. NR2F2 homodimers inhibit arterial differentiation in venous ECs through direct binding to the promoter regions of the Notch target genes HEY1 and HEY2 (HEY1/2), whereas NR2F2/PROX1 heterodimers lack this inhibitory effect, resulting at least in part in non-canonical HEY1/2 expression in LECs. Furthermore, NR2F2/PROX1 heterodimers actively induce or are permissive for the expression of a major subset of LEC-specific genes. In addition to NR2F2/PROX1 heterodimerisation, the expression of HEY1 and some of these LEC-specific genes is dependent on PROX1 DNA binding. Thus, NR2F2 homodimers in venous ECs and NR2F2/PROX1 heterodimers in LECs differentially regulate EC subtype-specific genes and pathways, most prominently the Notch target genes HEY1/2. This novel mechanistic insight could pave the way for new therapeutic interventions for vascular-bed-specific disorders. © 2013. Published by The Company of Biologists Ltd. Source

Aranguren X.L.,Molecular and Vascular Biology Research Unit
Blood | Year: 2013

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. Source

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