Angiogenesis and osteogenesis are not directly coupled during calvarial bone regeneration. Early vascular sprouting does not coincide with osteoprogenitor invasion. Osteoprogenitors from the periosteum give rise to osteoblasts at the injured bone edge, while microvessels inside the lesion are not associated with osteoprogenitors. Subsequently, osteogenic cells invade the vascularized lesion as a multicellular layer, promoting regenerative ossification. Vascular sprouting and remodeling dynamically adjust blood flow to accommodate bone growth. Single-cell profiling shows mesenchymal stromal cell heterogeneity comparable to femoral fractures, with increased cell types promoting bone regeneration. Angiogenesis and hypoxia-related genes are slightly elevated, reflecting vascularized lesion ossification. Endothelial Notch and VEGF signaling alter vascular growth without affecting ossification. These findings have clinical implications for bone regeneration and bioengineering. Despite advances in understanding bone regeneration mechanisms, challenges in orthopedic surgery persist due to failed or delayed fracture healing and complications during bone repair. Segmental bone defects caused by trauma, infections, and tumors often result in significant disabilities. The reasons for failed bone regeneration and non-union fractures remain unclear. Bone repair involves complex cellular and molecular events orchestrated by various mediators and signaling factors. In long bones, fracture healing involves several stages, starting with hematoma formation, followed by reparative and remodeling. Critical steps include robust vascularization and recruitment of mesenchymal and osteogenic cells. Vascularization and osteogenesis are closely coupled through specialized blood vessels that provide paracrine signals to coordinate osteoprogenitor migration and differentiation. The signaling interactions regulating co-invasion of osteoprogenitors with blood vessels during fracture repair are poorly understood. Candidate mediators include components of the VEGF and HIF pathways, Notch, and PDGFRβ signaling. PDGFRβ has been suggested to be a critical functional driver for mesenchymal skeletal stem cell activation, migration, and angiotropism during bone repair. In the initial phase, the hematoma creates a signaling milieu to attract inflammatory cells. While macrophages clear necrotic tissue, inflammatory cells release chemotactic and growth factors to recruit various cell types, including vascular endothelial cells, mesenchymal stromal cells (MSCs), and fibroblasts. At the fracture site, MSCs proliferate and differentiate into osteoprogenitors and osteoblasts to promote bone regeneration. Long bone fractures typically involve interfragmentary strain that induces chondroid soft callus formation. Hypertrophic chondrocytes secrete cytokines and growth factors to attract vascular endothelial cells and osteoprogenitors. Sprouting capillaries originate from the periosteal and intramedullary vasculature and infiltrate the avascular callus in close association with osteoprogenitors to promote callus remodeling and endochondAngiogenesis and osteogenesis are not directly coupled during calvarial bone regeneration. Early vascular sprouting does not coincide with osteoprogenitor invasion. Osteoprogenitors from the periosteum give rise to osteoblasts at the injured bone edge, while microvessels inside the lesion are not associated with osteoprogenitors. Subsequently, osteogenic cells invade the vascularized lesion as a multicellular layer, promoting regenerative ossification. Vascular sprouting and remodeling dynamically adjust blood flow to accommodate bone growth. Single-cell profiling shows mesenchymal stromal cell heterogeneity comparable to femoral fractures, with increased cell types promoting bone regeneration. Angiogenesis and hypoxia-related genes are slightly elevated, reflecting vascularized lesion ossification. Endothelial Notch and VEGF signaling alter vascular growth without affecting ossification. These findings have clinical implications for bone regeneration and bioengineering. Despite advances in understanding bone regeneration mechanisms, challenges in orthopedic surgery persist due to failed or delayed fracture healing and complications during bone repair. Segmental bone defects caused by trauma, infections, and tumors often result in significant disabilities. The reasons for failed bone regeneration and non-union fractures remain unclear. Bone repair involves complex cellular and molecular events orchestrated by various mediators and signaling factors. In long bones, fracture healing involves several stages, starting with hematoma formation, followed by reparative and remodeling. Critical steps include robust vascularization and recruitment of mesenchymal and osteogenic cells. Vascularization and osteogenesis are closely coupled through specialized blood vessels that provide paracrine signals to coordinate osteoprogenitor migration and differentiation. The signaling interactions regulating co-invasion of osteoprogenitors with blood vessels during fracture repair are poorly understood. Candidate mediators include components of the VEGF and HIF pathways, Notch, and PDGFRβ signaling. PDGFRβ has been suggested to be a critical functional driver for mesenchymal skeletal stem cell activation, migration, and angiotropism during bone repair. In the initial phase, the hematoma creates a signaling milieu to attract inflammatory cells. While macrophages clear necrotic tissue, inflammatory cells release chemotactic and growth factors to recruit various cell types, including vascular endothelial cells, mesenchymal stromal cells (MSCs), and fibroblasts. At the fracture site, MSCs proliferate and differentiate into osteoprogenitors and osteoblasts to promote bone regeneration. Long bone fractures typically involve interfragmentary strain that induces chondroid soft callus formation. Hypertrophic chondrocytes secrete cytokines and growth factors to attract vascular endothelial cells and osteoprogenitors. Sprouting capillaries originate from the periosteal and intramedullary vasculature and infiltrate the avascular callus in close association with osteoprogenitors to promote callus remodeling and endochond