Angiogenesis is a critical parameter to consider for the development of tissue-engineered bone substitutes. The challenge is to promote sufficient vascularization in the bone substitute to prevent cell death and to allow its efficient integration. The capacity of nacre extract to restore the osteogenic activity of osteoarthritis osteoblasts has already been demonstrated. However, their angiogenic potential on endothelial progenitor cells (EPCs) was not yet explored. Therefore, the current study aimed at investigating if nacreous molecules affect EPC behavior. The gene and protein expression levels of endothelial cell-specific markers were determined in EPCs cultivated in presence of a nacre extract (Ethanol Soluble matrix (ESM) at two concentrations: 100µg/mL and 200µg/mL (respectively abbreviated ESM100 and ESM200)). Cell functionality was explored by proangiogenic factors production and in vitro tube formation assay. ESM200 increased the expression of some endothelial cell-specific genes. The in vitro tube formation assay demonstrated that ESM200 stimulated tubulogenesis affecting angiogenic parameters. We demonstrated that a stimulation with 200µg/mL of ESM increased angiogenesis key elements. This in vitro study strongly highlights the proangiogenic effect of ESM. Due to its osteogenic properties, previously demonstrated, ESM could constitute the key element to develop an ideal prevascularized bone substitute.