Oxidative DNA damage contributes to replicative senescence. We explored the mechanism by which angiotensin II (Ang II) induces senescence in human vascular endothelial cells (HUVECs). Following weeklong incubation with Ang II, cell senescence, apoptosis, reactive oxygen species (ROS) content and mitochondrial membrane potential (MMP) were measured by β-galactosidase, annexin V/propidium iodide, DCFH-DA and rhodamine 123 staining, respectively. The protein levels of telomerase reverse transcriptase (TERT), UCP2, Akt, phosphor (p)-Akt, c-myc, and p53 were assessed by immunoblot. LY294002 was applied to inhibit PI3K/Akt signaling. Ang II induced HUVEC senescence and apoptosis, and increased ROS content and depolarization of MMP in a dose-dependent manner. Ang II further elevated protein levels of TERT from 0.006 ± 0.041 at baseline, to 0.480 ± 00.031 in the presence of 10 µM Ang II, UCP2 from 0.297 ± 0.051 to 2.512 ± 0.024, p-Akt from 0.012 ± 0.024 to 0.874 ± 0.015, c-myc from 0.521 ± 0.015 to 1.064 ± 0.025, and p53 from 0.035 ± 0.047 to 1.195 ± 0.029 (all P < 0.01, vs. baseline). LY294002 pre-treatment significantly alleviated Ang II-induced HUVEC senescence, and partly reversed the elevation of TERT, UCP2, p-Akt, c-myc and p53 protein levels. PI3K/Akt/UCP2 signaling may be involved in cell senescence and apoptosis induced by Ang II in HUVECs.