Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

Table 1

Gene delivery of VEGF and BMPs.

Authors	BMPs	Vectors; (cell-type)	Models	Expression in combination group	Ratio; (VEGF/BMP)	Bone formation in combined delivery group
Peng et al. 2002 [19]	BMP4	Retroviral vectors; (MDSCs); Cell-expressing BMP4 or VEGF	Mice; Intramuscular (4 weeks); Calvarial defect (3/6 weeks); Calvarial defect (3 weeks)	BMP4: 115 ± 20 ng/10^6 cells/24 h; VEGF: 214 ± 35 ng/10^6 cells/24 h (>4 weeks)	Cell ratio: 1 : 5; 1 : 5; 1 : 5 (group 1, G1); 1 : 1 (group 2, G2); 5 : 1 (group 3, G3)	Enhanced (compared to BMP4 alone); Enhanced (compared to BMP4 alone); Increased (compared to G3); Increased (compared to G3); Decreased (compared to G1/2); [19]
Peng et al. 2005 [20]	BMP2	Retroviral vectors; (MDSCs); Cell-expressing BMP2 or VEGF	Mice; Intramuscular (4 weeks); Calvarial defect (3/6 weeks); Calvarial defect (3 weeks)	BMP2: 250 ng/10^6 cells/24 h; VEGF: 200 ng/10^6 cells/24 h (>4 weeks)	Cell ratio: 1 : 5; 1 : 5; 1 : 5 (group 1, G1); 1 : 1 (group 2, G2); 5 : 1 (group 3, G3)	Enhanced (compared to BMP2 alone); Enhanced (compared to BMP2 alone); Increased (compared to G3); Increased (compared to G3); Decreased (compared to G1/2); [20]
Samee et al. 2008 [21]	BMP2	Plasmid vectors; (human periosteal cells); Cell-expressing BMP2 and/or VEGF	Mice; Intramuscular (4/8 weeks)	BMP2: ~600–950 ng/10^6 cells/12–48 h; VEGF: ~1.5–7.5 ng/10^6 cells/12–48 h; (within 5 weeks)	Plasmid ratio in cotransfection: 1 : 1	Enhanced at 4 weeks; (compared to BMP2 alone); No significant difference at 8 weeks; (compared to BMP2 alone); [21]
Li et al. 2009 [22]	BMP4	Retroviral vectors; (C2C12 and NIH/3T3 cells); Cell-expressing BMP4 and/or VEGF	Mice; Intramuscular (3-5weeks)	C2C12: BMP4: 105 ± 10 ng/10^6 cells/24 h,; VEGF: 152 ± 20 ng/10^6 cells/24 h NIH/3T3: BMP4: 98 ± 5 ng/10^6 cells/24 h; VEGF: 128 ± 12 ng/10^6 cells/24 h; (Retroviral vectors ratio 1 : 1)	Retroviral vectors ratio in cotransfection: 1 : 1; 1 : 5; 1 : 50	Inhibited (compared to BMP4 alone); More detrimental effect; Detrimental effect; Less detrimental effect (compared to BMP4 alone); [22]
Cui et al. 2010 [23]	BMP6	Plasmid vectors; (cloned mouse osteoprogenitor cells); Cell-expressing BMP6 and/or VEGF	Mice; Subcutaneous (2/3 weeks)	BMP6: ~1.8–18 ng/10^6 cells/24 h; VEGF: ~0.12–12 ng/10^6 cells/24 h; (within 2 weeks)	VEGF/BMP6; gene (1 : 1); incorporated in plasmid constructs	Enhanced (compared to BMP6 alone); [23]
Xiao et al. 2011 [24]	BMP2	Adenoviruse vectors; (rabbit bone marrow stromal cells); Cell-expressing BMP2 or VEGF	Rabbit; Orbital defects (4/8/16 weeks)	BMP2: ~300 pg/10^6 cells/24 h; VEGF: ~300 pg/10^6 cells/24 h; (within 8 weeks)	Cell ratio: 1 : 4; (VEGF/BMP ratio 1 : 1)	Enhanced (compared to BMP2 alone); [24]

MDSCs = mouse muscle-derived stem cells, C2C12 cells = mouse myoblasts, and NIH/3T3 cells = mouse fibroblasts.