Recently several laboratories have reported that radiation induces senescence in endothelial cells. Senescent cells can secrete multiple growth-regulatory proteins, some of which affect tumor growth, survival, invasion or angiogenesis. The purpose of this study was to explore the mechanisms of radiation-induced senescence and its effects on angiogenesis in human umbilical vein endothelial cells (HUVECs). HUVECs were either pretreated with or without PS1145 prior to irradiation with 0–8 Gy. PS1145 is a novel, highly specific small-molecule inhibitor of nuclear factor kappa B essential modulator (NEMO). MTT assays showed that in HUVECs untreated with PS1145, there was an increase in the number of radiation-induced senescence-like endothelial cells 5 days after 8 Gy irradiation, while pretreatment with PS1145 significantly ameliorated the induction in senescence of HUVECs compared to the control group. Electrophoretic mobility shift assay (EMSA) showed that pretreatment with PS1145 inhibited the radiation-induced NF-κB activation, which regulates cell fate in response to genotoxic stress. In addition, Western blotting demonstrated less translocation of p65 from cytoplasm to nucleus. Furthermore, real-time polymerase chain reaction (PCR) showed that pretreatment with PS1145 inhibited the increase of mRNA expressions of interleukin-6 (IL-6) and p53-induced death domain (PIDD) protein, which have been show to play crucial roles in both senescence and apoptosis (P < 0.05). TUNEL staining revealed an increase in apoptotic HUVECs in the group pretreated with PS1145 after irradiation. The series of functional assays further showed that radiation-induced senescence-like HUVECs had malfunctions in migration, invasion and formation of capillary-like structures, compared with the sham-irradiated and untreated, irradiated groups. Taken together, these findings indicate that the angiogenic capacity of radiation-induced senescence-like HUVECs decreased, and that irradiation caused vascular endothelial cells to gain a senescence-like phenotype through the DSB/NEMO/NF-κB signal pathway. The data suggests that NEMO may be a critical switch that regulates cellular senescence and apoptosis caused by exposure to radiation, and provides new clues for the clinical potential of the combination of radiotherapy and angiogenesis inhibitors.