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

doi:10.1016/j.isci.2023.107455

Region-specific sympatho-adrenergic regulation of specialized vasculature in bone homeostasis and regeneration

iScience. 2023 Jul 22;26(9):107455. doi: 10.1016/j.isci.2023.107455. eCollection 2023 Sep 15.

Authors

Hao-Kun Xu^{1

2}, Jie-Xi Liu¹, Chen-Xi Zheng¹, Lu Liu^{1

3}, Chao Ma¹, Jiong-Yi Tian¹, Yuan Yuan^{1

4}, Yuan Cao^{1

3}, Shu-Juan Xing¹, Si-Ying Liu³, Qiang Li⁵, Ya-Juan Zhao⁵, Liang Kong⁶, Yong-Jin Chen⁵, Bing-Dong Sui¹

Affiliations

¹ 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.
² Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
³ Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
⁴ Exercise Immunology Center, Wuhan Sports University, Wuhan, Hubei 430079, China.
⁵ Department of General Dentistry & Emergency, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
⁶ Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Abstract

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.

Keywords: Molecular neuroscience; Orthopedics; Vascular anatomy.