Objective - Angiogenesis is required for tissue regeneration and pro-angiogenic therapy is used to improve tissue perfusion during angiopathy and arteriosclerosis. The endothelial angiogenic function is a consequence of the execution of a complex phenotypic program. We hypothesized that global alteration of gene expression can be used to switch the endothelial phenotype from a resting to a pro-angiogenic state. To study this aspect, we characterized the function of nuclear repressor complexes in human umbilical vein endothelial cells (HUVEC) as well as in organ culture of mouse aortic tissue from different knockout mice. 

Results – Screening of HUVECs revealed a particular high expression of the repressors NCoR1 and SMRT. Knockdown of these genes by siRNA demonstrated that loss of NCoR1, but not SMRT increases the endothelial cell angiogenic capacity as determined by spheroid out-growth assay. Contrary, proliferation and migration of NCoR1 deficient endothelial cells was decreased. To determine the underlying mechanism, RNAseq was performed. Loss of NCoR1 significantly upregulated 1200 different genes including VEGFR2, PTGS2 and THBS2. Accordingly, KEGG analysis indicates a positive correlation between NCoR1 and the PI3K-Akt- as well as the TGF-beta signalling pathway.   

Conclusion – NCoR1 is an interesting target allowing the positive modulation of pathophysiological angiogenesis related processes such as diabetes or atherosclerosis.