骨骼中的血管生成独特，涉及特殊信号。无论是通过软骨内骨化还是骨软骨化，骨骼都是高度血管化的组织。长骨经历一系列被称为软骨内成骨的过程。血管生成发生在软骨骨的形成过程中，由多种细胞和因子介导。最初无血管的软骨模板被来自附近骨下殿骨的血管侵入，这是由于成熟软骨细胞分泌的血管生成化学物质的作用。一氧化氮素血管内皮生长因子（VEGF）是多种血管生成分子中的一个重要调节因子，它是新骨基质的血管入侵、软骨重塑和骨化的重要调节因子；血管内皮生长因子的产生通过纤维母细胞生长因子（FGFs）刺激，促进软骨细胞增殖和肥大。NOTCH信号通路控制骨成熟和再生中的血管形成，而缺氧诱导因子1 alpha（HIF1-α）通过转变为无氧代谢促进软骨细胞发育。为了控制骨重塑和修复，成骨细胞释放血管生成因子，而内皮细胞则分泌血管生成因子。一些器官中特定功能血管分化的最好例子之一就是骨骼系统。骨骼中的一种毛细血管内皮细胞亚群调节成骨前体细胞的活性，进而影响发育过程中以及成人体内的骨形成。血管生成和成骨密切相关，它们之间的相互作用对于保证骨形成和骨稳态至关重要。此外，包括炎症、癌症和衰老在内的病理过程中涉及了骨内皮细胞和血管生成因子。因此，研究和理解这些机制是至关重要的，因为涉及的分子和因子可能代表新的先进治疗的关键目标。Copyright © 2023 Ribatti and d’Amati.

Angiogenesis in the bone is unique and involves distinctive signals. Whether they are created through intramembranous ossification or endochondral ossification, bones are highly vascularized tissues. Long bones undergo a sequence of processes known as endochondral osteogenesis. Angiogenesis occurs during the creation of endochondral bone and is mediated by a variety of cells and factors. An initially avascular cartilage template is invaded by blood vessels from the nearby subchondral bone thanks to the secreted angiogenic chemicals by hypertrophic chondrocytes. Vascular endothelial growth factor (VEGF), one of several angiogenic molecules, is a significant regulator of blood vessel invasion, cartilage remodeling, and ossification of freshly created bone matrix; chondrocyte proliferation and hypertrophy are facilitated by the production of VEGFA and VEGF receptor-2 (VEGFR-2), which is stimulated by fibroblast growth factors (FGFs). NOTCH signaling controls blood capillaries formation during bone maturation and regeneration, while hypoxia-inducible factor 1 alpha (HIF1-a) promotes chondrocyte development by switching to anaerobic metabolism. To control skeletal remodeling and repair, osteogenic cells release angiogenic factors, whereas endothelial cells secrete angiocrine factors. One of the better instances of functional blood vessels specialization for certain organs is the skeletal system. A subpopulation of capillary endothelial cells in the bone regulate the activity of osteoprogenitor cells, which in turn affects bone formation during development and adult homeostasis. Angiogenesis and osteogenesis are strictly connected, and their crosstalk is essential to guarantee bone formation and to maintain bone homeostasis. Additionally, pathological processes including inflammation, cancer, and aging include both bone endothelial cells and angiocrine factors. Therefore, the study and understanding of these mechanisms is fundamental, because molecules and factors involved may represent key targets for novel and advanced therapies.Copyright © 2023 Ribatti and d’Amati.