SU5416 delays wound healing through inhibition of TGF-beta 1 activation.
Angiogenesis, development of new blood vessels, is essential for wound healing and tumor growth. A potentially important side effect of anti-angiogenic therapy can be delayed wound healing. In this study we address this issue by using a novel in vivo method utilizing fibrin containing dual porous plexiglass chambers (Fibrin Z-Chambers; F-ZC) to investigate wound healing in rats administered with SU5416 (inhibitor of Flk-1 and Flt-1, at 20 mg/kg i.p.). SU5416 treated F-ZCs developed 45% less granulation tissue (p = 0.0076) and showed a 10% reduction in microvessel density (p = 0.0009) than controls treated with drug carrier alone. The granulation tissue showed distinctly decreased collagen deposition (p = 0.0006) in SU5416 treated animals that was associated with 90% reduction in active TGF-beta 1 level. We found that tissue transglutaminase (TG), a cross-linking enzyme involved in TGF-beta 1 activation and matrix stabilization, was inhibited by SU5416. These results suggest that SU5416 delays wound healing by reducing matrix synthesis and stabilization through inhibition of TGF-beta 1 activation. This study was made feasible via the development of a unique method to study anti-angiogenic compounds that provides highly reproducible and quantitative results. Further studies are needed to evaluate in vivo whether anti-angiogenic agents alter wound healing.
Haroon
Zishan A
ZA
Box 3455, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA. zishan.haroon@sri.com
Amin
Khalid
K
Saito
Wilfred
W
Wilson
William
W
Greenberg
Charles S
CS
Dewhirst
Mark W
MW
D000255:Adenosine Triphosphate / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1; D011503:Transglutaminases / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects*
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C116890:Semaxinib; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D003094:Collagen; D011503:Transglutaminases; D011505:Protein-Tyrosine Kinases