Angiogenic growth factor synergism in a murine tissue engineering model of angiogenesis and adipogenesis.
De novo tissue generation stimulated by three angiogenic growth factors administered in a factorial design was studied in an in vivo murine tissue engineering chamber. A silicone chamber was implanted around the epigastric pedicle and filled with Matrigel with 100 ng/ml of recombinant mouse vascular endothelial growth factor-120 (VEGF120), recombinant human basic fibroblastic growth factor (FGF-2), or recombinant rat platelet-derived growth factor-BB (PDGF-BB) added as single, double, or triple combinations. Angiogenesis, supporting tissue ingrowth, and adipogenesis were assessed at 2 and 6 weeks by immunohistochemistry and morphometry. At 2 weeks angiogenesis was synergistically enhanced by VEGF120 + FGF-2 (P = 0.019). FGF-2 (P = 0.008) and PDGF-BB (P = 0.01) significantly increased connective tissue/inflammatory cell infiltrate (macrophages, pericytes, and preadipocytes) in double and triple combinations compared with control. At 6 weeks sequential addition of growth factors increased the percent volume of adipose tissue (P < 0.0005, each main effect), with a synergistic increase in adipose tissue in combination treatments (P < 0.0005). Groups containing 300 ng/ml of single growth factors produced significantly less adipose tissue than the triple growth factor combination (P < 0.0005, VEGF120 and PDGF-BB; P < 0.001, FGF-2). In conclusion, angiogenic growth factor combinations increased early angiogenesis and cell infiltration resulting in synergistically increased adipose tissue growth at 6 weeks. Two way and higher level synergies are likely to be important in therapeutic applications of angiogenic growth factors.
Bernard O'Brien Institute of Microsurgery, St Vincent's Hospital, 42 Fitzroy St., Fitzroy, Victoria, 3065, Australia.
John A
JA
Rophael
Randall O
RO
Craft
Jason A
JA
Palmer
Alan J
AJ
Hussey
Gregory P L
GP
Thomas
Wayne A
WA
Morrison
Anthony J
AJ
Penington
Geraldine M
GM
Mitchell
D050156:Adipogenesis / Q000187:drug effects*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology*; D023822:Tissue Engineering
D043925:Angiogenesis Inducing Agents; D011994:Recombinant Proteins