TY  - JOUR
A1  - Teichmann, Tom
A1  - Malacarne, Pedro Felipe
A1  - Zehr, Simonida
A1  - Günther, Stefan
A1  - Pflüger-Müller, Beatrice
A1  - Warwick, Timothy
A1  - Brandes, Ralf
T1  - NCoR1 limits angiogenic capacity by altering Notch signaling
T2  - Journal of molecular and cellular cardiology
N2  - Highlights
• NCoR1 is the most highly expressed endothelial corepressor.
• Loss of NCoR1 promotes angiogenic function in endothelial cells.
• Loss of NCoR1 promotes a tip cell position during angiogenic sprouting.
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
KW  - NCoR1
KW  - Endothelial cells
KW  - Notch signaling
KW  - Angiogenesis
Y1  - 2024
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/82947
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-829477
SN  - 0022-2828
VL  - 188
SP  - 65
EP  - 78
PB  - Elsevier
CY  - Amsterdam
ER  -