Table 4 Summary of skeletal and systematic diseases associated with vasculature pathological alterations

Aging

• Reduction of type H EC quantity and osterix-positive osteoprogenitor abundance.

• Accumulation of defective HSCs and alterations in bone marrow stroma.

^8,206,207

Osteoporosis

• Estrogen decrease causes EC dysfunction, leads to alterations of bone perfusion and bone mass.

• Secondary risk factors like glucocorticoid inhibits PDGF-BB, leads to blood flow reduction and osteogenesis impairment.

^141,144,206

Osteoarthritis

• The preosteoclasts secrete an excessive amount of PDGF-BB, mediating the development of aberrant subchondral bone angiogenesis.

• Vascular signal production prompts mTORC1 activation in eroding articular cartilage.

• Elevated pro-angiogenic factors mediate inflammatory infiltration, structural damage and nociceptive transmission in OA.

^143,216,218

Fracture Nonunion

• Abnormal vasculature reduces local bone nutrient sources, increases metabolite deposition and impedes fracture healing efficiency.

• Vascular dysfunction exerts detrimental impacts on osteogenic differentiation process and disruption of osteoblast-osteoclast equilibrium.

• Inflammatory cells secret and recruit negative regulators towards local injury sites.

^223,225,227

Avascular Necrosis

• EC damage and grume formation cause blood flow interruption and osteocyte death, articular surface collapse.

• Decreased EC abundance and pro-angiogenic factor expression lead to decreased migration ability and increased senescence tendency.

^232,233,234

Heterotopic Ossification

• Mesenchymal progenitors function as the major niche in expressing VEGF-A for accelerating ectopic bone formation.

• Activation of modulators (BMPs and chondrogenic transcription factors) and loss of mineralization inhibitors (pyrophosphate) lead to HO-vascular calcification.

^{236,237,238,239}

Diabetes Mellitus

• Microangiopathy causes impaired vasoconstriction and blood flow.

• Hyperglycemia diverts BMSCs to a metabolically stressed adipogenic pathway instead of osteogenesis.

• AGEs leads to EC dysfunction, pro-angiogenic factor deficiency and a cross-linked imbalance of bone-vessel equilibrium.

^242,243,244

Osseous Neoplasm/Metastasis

• Matrix-abundant vascular microenvironment within bone provides fertile soils for metastatic growth.

• PDGF-B from vessels provides arteriolar niches for HSCs and DTCs long-term maintaining.

• Blood flow decline within bone conduce to interactions between tumor cells and skeletal ECs, thus developing into macrometastasis.

^252,253,254