BACKGROUND: Hypoxia is a critical contributor to increased risks of cardiovascular diseases, including atherosclerosis, but the detailed mechanism that hypoxia leads to atherosclerosis remains unknown. METHODS: Pregnant rats were treated with hypoxia (10.5% oxygen) during pregnancy, and HUVEC cells treated with 1% of oxygen. Blood lipids were tested at fetal stage and adult stage of offspring rats; the level of pro-inflammatory cytokines of HUVEC and offspring rats were investigated, and HIF-1alpha and NFkappaB mRNA level were also measured by Q-PCR and Elisa. RESULTS: We found that TC, LDL-C, ox-LDL-C, and the receptors of ox-LDL-C (lox-1) of the adult offspring were significantly higher than that of the control, while HDL-C was significantly reduced in hypoxia group. The internal elastic lamina was blocked by smooth muscle cells; and the migration of smooth muscle cells into the intima were observed in hypoxia offspring. Luciferase reporter gene experiment showed that HIF-1alpha activated NFkappaB transcription at four discrete binding sites of NFkappaBp65 promoter, although there was no obvious difference among the four discrete binding sites. Using transfection of pCDNA3.1-HIF-1alpha on HUVEC cells, HIF-1alpha significantly activated NFkappaB transcription at hypoxic conditions (1% O2), and concurrent with increased expression of IL-1beta and TNF-alpha. CONCLUSION: Hypoxia during pregnancy activated NFkappaB transcription to induce pro-inflammatory cytokines, leading to the early stage of atherosclerosis.