MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity

• Published in: Nature communications Vol. 8; no. 1; pp. 16003 - 11
• Main Authors: Yang, Mi, Li, Chang-Jun, Sun, Xi, Guo, Qi, Xiao, Ye, Su, Tian, Tu, Man-Li, Peng, Hui, Lu, Qiong, Liu, Qing, He, Hong-Bo, Jiang, Tie-Jian, Lei, Min-Xiang, Wan, Mei, Cao, Xu, Luo, Xiang-Hang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 14/19; 38; 38/61; 692/4019/592/16; Aging; Angiogenesis; Animals; Antagomirs - genetics; Antagomirs - metabolism; Aptamers; Aptamers, Nucleotide - genetics; Aptamers, Nucleotide - metabolism; Bone and Bones - blood supply; Bone and Bones - metabolism; Bone and Bones - pathology; Bone Density; Bone growth; Bone loss; Bone mass; Cdc4 protein; Clusters; Coupling; Endothelial cells; Endothelium; F-Box-WD Repeat-Containing Protein 7 - genetics; F-Box-WD Repeat-Containing Protein 7 - metabolism; Gene Expression Regulation, Developmental; Humanities and Social Sciences; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Mice; Mice, Knockout; MicroRNAs - agonists; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Targeted Therapy; multidisciplinary; Neovascularization, Physiologic - genetics; Osteogenesis; Osteogenesis - genetics; Osteoporosis; Osteoporosis - genetics; Osteoporosis - metabolism; Osteoporosis - pathology; Osteoporosis - therapy; Platelet Endothelial Cell Adhesion Molecule-1 - agonists; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Procollagen-proline dioxygenase; Prolyl Hydroxylases - genetics; Prolyl Hydroxylases - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Science; Science (multidisciplinary); Sialoglycoproteins - agonists; Sialoglycoproteins - genetics; Sialoglycoproteins - metabolism; Signal Transduction; Therapeutic targets; Transmembrane domains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms16003

A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31 hi Emcn hi ), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31 hi Emcn hi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31 hi Emcn hi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31 hi Emcn hi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31 hi Emcn hi vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31 hi Emcn hi vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis. H-type endothelium, defined by the high expression of CD31 and endomucin, is found in the bone where it promotes angiogenesis and osteogensis. Here Yang et al . show that the miR-497∼195 cluster regulates the generation and maintenance of the H-type endothelium by controlling the levels of Notch regulator Fbxw7 and the HIF regulator P4HTM.