Vc. Lees et al., ANGIOGENESIS IN A DELAYED REVASCULARIZATION MODEL IS ACCELERATED BY ANGIOGENIC OLIGOSACCHARIDES OF HYALURONAN, Laboratory investigation, 73(2), 1995, pp. 259-266
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.