ANGIOGENESIS IN A DELAYED REVASCULARIZATION MODEL IS ACCELERATED BY ANGIOGENIC OLIGOSACCHARIDES OF HYALURONAN

BACKGROUND: A delayed revascularisation model has been used to assess the angiogenic activity of hyaluronan fragments on impaired wound heal ing. EXPERIMENTAL DESIGN: Revascularisation of single, full thickness skin autografts in rats was delayed by subjecting isolated grafts to a sublethal cryoinjury (freeze injury) before implantation. Hyaluronan fragments were delivered to the grafts using slow release pellets (eth ylene vinyl acetate copolymer). Rates of release were measured in vitr o by ELISA. The angiogenic response to the application of 100 mu g of low (1 to 4 kDa) molecular weight hyaluronan and 100 mu g of medium (3 3 kDa) molecular weight hyaluronan was tested in separate groups of 15 rats and was compared with unstimulated cryoinjured controls (n = 40) . The effect of low (1 to 4 kDa) molecular weight hyaluronan on uninju red grafts was also investigated. Return of graft blood flow was measu red on anesthetised animals over a 10-day period using laser Doppler f lowmetry and Xe-133 clearance. Quantitative histologic assessment of t he graft vasculature was performed on Days 3, 7, and 10 after implanta tion. RESULTS: The 1- to 4-kDa hyaluronan fragments increased blood fl ow (p < 0.001), as measured by both flow measuring techniques, and inc reased graft vessel growth, as assessed histologically at each of the three time points (p < 0.05). By contrast, the 33-kDa fragments had no such effect on graft blood flow or vessel growth. Low molecular weigh t hyaluronan had no effect on either graft blood flow or on vessel gro wth in uninjured skin grafts. CONCLUSIONS: The hypothesis that there m ay be physiologic regulation of angiogenesis by hyaluronan and its met abolites is supported by the results of these studies. The data provid e further evidence of the utility of the cryoinjured graft model for t he study of in vivo angiogenesis.