Region-specific sympatho-adrenergic regulation of specialized vasculature in bone homeostasis and regeneration
Hao-Kun Xu,
Jie-Xi Liu,
Chen-Xi Zheng,
Lu Liu,
Chao Ma,
Jiong-Yi Tian,
Yuan Yuan,
Yuan Cao,
Shu-Juan Xing,
Si-Ying Liu,
Qiang Li,
Ya-Juan Zhao,
Liang Kong,
Yong-Jin Chen,
Bing-Dong Sui
Affiliations
Hao-Kun Xu
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Jie-Xi Liu
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Chen-Xi Zheng
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Lu Liu
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Chao Ma
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Jiong-Yi Tian
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Yuan Yuan
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Exercise Immunology Center, Wuhan Sports University, Wuhan, Hubei 430079, China
Yuan Cao
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Shu-Juan Xing
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Si-Ying Liu
Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Qiang Li
Department of General Dentistry & Emergency, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Ya-Juan Zhao
Department of General Dentistry & Emergency, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Liang Kong
Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Corresponding author
Yong-Jin Chen
Department of General Dentistry & Emergency, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Corresponding author
Bing-Dong Sui
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China; Corresponding author
Summary: Type H vessels couple angiogenesis with osteogenesis, while sympathetic cues regulate vascular and skeletal function. The crosstalk between sympathetic nerves and type H vessels in bone remains unclear. Here, we first identify close spatial connections between sympathetic nerves and type H vessels in bone, particularly in metaphysis. Sympathoexcitation, mimicked by isoproterenol (ISO) injection, reduces type H vessels and bone mass. Conversely, beta-2-adrenergic receptor (ADRB2) deficiency maintains type H vessels and bone mass in the physiological condition. In vitro experiments reveal indirect sympathetic modulation of angiogenesis via paracrine effects of mesenchymal stem cells (MSCs), which alter the transcription of multiple angiogenic genes in endothelial cells (ECs). Furthermore, Notch signaling in ECs underlies sympathoexcitation-regulated type H vessel formation, impacting osteogenesis and bone mass. Finally, propranolol (PRO) inhibits beta-adrenergic activity and protects type H vessels and bone mass against estrogen deficiency. These findings unravel the specialized neurovascular coupling in bone homeostasis and regeneration.
