Bone tissue engineering has generated promising results in bone defect repair, but is limited by the inherently poor nutrient supply to nonvascularized tissue-engineered bone grafts. In this study, we investigated the delivery of vascular endothelial growth factor (VEGF) and the effect on in vitro cultured human umbilical vein endothelial cells (HUVECs), in an attempt to provide experimental basis for promoting the vascularization of tissue-engineered bone grafts. A mechanical stimulator was developed to generate a periodic compressive load analogous to goat locomotor characteristics, simulating the mechanical stimulation applied on the fracture ends of the load-bearing bone. Poly-l-lysine-coated VEGF/alginate microspheres were combined with demineralized bone matrices into composites, and the in vitro release of VEGF from these composites was evaluated under periodic compression. The effect of the release media on HUVECs was also investigated. Compression slightly accelerated VEGF release at the early stage (<11 days) compared with noncompressed composites, although the release profiles of the two composite groups were generally similar. The released VEGF promoted HUVEC proliferation. In addition, the periodic compression applied on composites containing both HUVECs and VEGF/alginate microspheres promoted the expression of matrix metalloproteinases-2/9 in HUVECs. This study provides a model for investigating VEGF release under simulated in vivo biomechanical conditions and without the disadvantage of the rapid degradation of VEGF in in vivo investigation of VEGF release. The results also provide important guidelines for future in vivo experiments.