Fig. 10.

Mechanisms coupling angiogenesis and osteogenesis. a) Type-H vessels are mainly located at the metaphysis and endosteum, which are rich in osteoprogenitors and MSCs. Several factors have been proved to proliferate type-H ECs, including PDGF-BB secreted by preosteoclasts and TRAP⁺ macrophages (blue arrows), SLIT3 secreted by osteoblasts and osteoclasts (green arrows), and VEGF released by osteoblasts, osteoclasts and chondrocytes (pink arrows). The formation of type-H ECs will further facilitate osteogenesis by bone-producing cells (dotted arrow). b) The influence of type-H ECs on osteogenesis cells. Blood fluid stress can activate notch/Dll4 signaling, which can further induce the release of Noggin. Noggin promotes the proliferation and differentiation of osteoprogenitors and the maturation of chondrocytes. In a hypoxic environment, HIF-1α is upregulated in ECs and osteoprogenitors, which can trigger the expression of VEGF and promote vessel growth. Besides, the activation of HIF-1α facilitates the self-renewal and proliferation of osteoprogenitors. Compared to type L, type-H ECs have a strong expression of multiple cytokines, including FGF1, TGFβ, and PDGF, which play essential roles in the osteoprogenitors' survival, proliferation, and differentiation.