Background <p>The survival and function of three-dimensional tissues critically depend on the establishment of a functional vascular network that ensures oxygen and nutrient supply and waste removal. Insufficient vascularization leads to hypoxia, metabolic stress, and cell death, making angiogenesis a fundamental requirement for successful tissue regeneration. This requirement is particularly evident in highly vascularized tissues such as bone, where vascular networks closely regulate tissue metabolism and repair.</p> Methods <p>Human adipose-derived mesenchymal stem cells (ASCs) were genetically modified to overexpress fibroblast growth factor 2 (FGF-2), a key regulator of angiogenesis. The angiogenic potential of these cells and the paracrine effects of their conditioned medium were subsequently evaluated, together with their effects on osteogenic differentiation to assess functional specificity.</p> Results <p>Overexpression of FGF-2 in ASCs enhanced endothelial cell migration and tube formation via paracrine mechanisms, in which elevated secretion of VEGFA and other angiogenic factors acted synergistically to promote angiogenesis. In contrast, osteogenic differentiation of ASCs was significantly inhibited by FGF-2 overexpression. Notably, <i>FGFR2</i> expression, the receptor for FGF-2, was selectively downregulated during osteogenic induction, suggesting that sustained FGF-2 signaling preferentially interferes with FGFR-mediated pathways associated with osteogenic maturation rather than with early proliferative responses.</p> Conclusion <p>Our results demonstrate that FGF-2–overexpressing ASCs function not as osteogenic effector cells but as a potent paracrine platform for angiogenesis. Their conditioned medium, enriched with FGF-2 and synergistic angiogenic factors, supports vascular network formation and indirectly enhances the regenerative microenvironment, highlighting its potential as a cell-free strategy for tissue regeneration.</p>