Hyperphosphatemia is an independent risk factor of cardiovascular events in the patients with chronic kidney disease. High phosphate can induce endothelial cell apoptosis, but the exact mechanism is not clear. This study fills this knowledge gap. Microarray analysis was used to identify differentially expressed gene profiles in human umbilical vein endothelial cells (HUVECs) in high phosphate (3.0mM) and normal phosphate (1.0mM) medium. Microarray informatics analysis was used to explore key pathways and genes. High phosphate-induced apoptosis is marked by annexin V-FITC/PI staining and cleavage of caspase-3. Immunoblotting and quantitative real-time PCR were performed to identify the microarray analysis. Our microarray informatics analysis reveals that the mitogen-activated protein kinase (MAPK) plays a key role. As suggested by gene coexpression network analysis, bone morphogenetic protein 4 (BMP4) gene is a potential key regulatory gene in high phosphate environment. Both the expressions of BMP4 protein and mRNA are decreased. Extracellular regulated protein kinases (ERKs) are activated, while the inhibition of ERK by U0126 increases the expression of BMP4. Both recombinant BMP4 protein pretreatment and U0126 pretreatment reduce the apoptosis of endothelial cells in simulated hyperphosphatemia. However, BMP4 protein pretreatment had no effect on the activation of ERK MAPK pathway. Our results indicate that the inhibition of ERK MAPK pathway protects endothelial cells from apoptosis by upregulating bone morphogenetic protein 4 in endothelial cells exposed to hyperphosphatemia. Our study provides potential molecular targets for developing new strategies to reduce the endothelial cell apoptosis induced by high phosphate.