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.
Rophael
John A
JA
Bernard O'Brien Institute of Microsurgery, St Vincent's Hospital, 42 Fitzroy St., Fitzroy, Victoria, 3065, Australia.
Craft
Randall O
RO
Palmer
Jason A
JA
Hussey
Alan J
AJ
Thomas
Gregory P L
GP
Morrison
Wayne A
WA
Penington
Anthony J
AJ
Mitchell
Geraldine M
GM
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