Hyperglycemia promotes vasculogenesis in choroidal neovascularization in diabetic mice by stimulating VEGF and SDF-1 expression in retinal pigment epithelial cells.
To investigate the influence of hyperglycemia on the severity of choroidal neovascularization (CNV) in diabetic mice, especially the involvement of bone marrow-derived cells (BMCs) and underlying molecular mechanisms. The mice were randomly divided into control group, diabetes group and diabetes treated with insulin group, which were laser treated to induce CNV. The CNV severity was evaluated by fundus fluorescein angiography, HE staining and choroidal flatmount. The BMCs recruitment and differentiation in CNV were examined in GFP chimeric mice by choroidal flatmount and immunofluorescence. The bone marrow-derived mesenchymal stem cells (BMSCs) recruitment and migration were tested in vivo and in vitro. VEGF and SDF-1 production in vivo and in vitro were tested by realtime PCR and ELISA. The CNV severity and expression of VEGF and SDF-1 were enhanced in DM mice compared with control mice and that insulin treatment decreased CNV severity in DM mice. The DM mice demonstrated more BMCs and bone marrow-derived mesenchymal stem cells (BMSCs) recruited and incorporated into CNV, increased ratio of BMCs expressing endothelial cell marker or macrophage marker, and up-regulated expression of VEGF and SDF-1 in CNV. Human BMSCs migration and expression of VEGF and SDF-1 in retinal pigment epithelial (RPE) cells increased when cultured under high glucose. This study suggested that hyperglycemia enhanced the expression of VEGF and SDF-1 in RPE cells, and promoted recruitment and incorporation of BMCs and affected differentiation of BMCs in CNV, which led to more severe CNV in diabetic mice.
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Yan
Y
Cai
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Xia
X
Li
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China. Electronic address: wangys003@126.com.
Yu-Sheng
YS
Wang
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Yuan-Yuan
YY
Shi
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Zi
Z
Ye
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Guo-Dong
GD
Yang
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Guo-Rui
GR
Dou
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Hui-Yuan
HY
Hou
Department of Orthodontics, School of Stomatology, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Nan
N
Yang
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China.
Xiao-Rui
XR
Cao
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, Shaanxi Province, People's Republic of China. Electronic address: luzfliuq@fmmu.edu.cn.
Zi-Fan
ZF
Lu
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001808:Blood Vessels / Q000502:physiology*; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D049452:Green Fluorescent Proteins
age-related macular degeneration; bone marrow-derived cells; diabetes mellitus; retinal pigment epithelial cells