Improved free vascular graft survival in an irradiated surgical site following topical application of rVEGF

Purpose: Wound healing disorders following surgery in preirradiated tissue are clinically well known and may even become more crucial with the increasing use of neoadjuvant chemoradiation protocols. Both the expression of vascular endothelial growth factor (VEGF) and endoglin (CD105) play a key role in neovascularization and wound healing after soft tissue grafts in irradiated and nonirradiated tissue. Modulation of neovascularization through the application of recombinant VEGF (rVEGF) may be a therapeutic option to reduce wound healing disorders in irradiated tissue. An experimental in vivo model was used to study the possible role of rVEGF for reduction of wound healing disorders and the promotion of neovascularization. Methods and Materials: A free myocutaneous gracilis flap was transplanted from the groin into the neck region of Wistar rats (weight 300-500 g) with and without previous irradiation of the neck region with 40 Gy: Group I (n = 7) radiotherapy alone; Group 2 (n = 14) flap transplantation alone and rVEGF; Group 3 (n = 14) radiotherapy, transplantation, and rVEGF. Time interval between irradiation and grafting was 10 +/- 1 day. 1.0 mug rVEGF/500 muL phosphate-buffered saline was applied s.c. intraoperatively and on Days 1 through 7. Neovascularization (CD105) and endogenous VEGF expression were analyzed by means of immunohistochemistry on Days 3, 5, 7, 14, and 28 postoperatively and quantified as labeling indices (LI). Results: After irradiation there was a continuous significant reduction of the cytoplasmic VEGF expression (mean LI: 0.018 +/- 0.048) compared with the nonirradiated control (mean LI: 0.042 +/- 0.006) (p < 0.001). VEGF expression after flap transplantation without irradiation after VEGF application was at a constantly higher level from Day 3 (mean LI: 0.044 +/- 0.01) to Day 28 postoperatively compared with the control group (Day 3, mean LI: 0.028 +/- 0.006) (p < 0.001). As an indication of increased neovascularization after the local application of rVEGF, a significantly increased expression of CD105 was found in the transition area and graft bed from Day 7 on (p < 0.001). After irradiation and grafting there was a significant overall increase in the VEGF- and CD105-expression throughout Day 28 after rVEGF in the transition area (p < 0.001). Conclusions: Whereas irradiation alone led to a downregulation of the endogenous VEGF expression, rVEGF application resulted in an increased expression and in a CD105 associated neovascularization after soft tissue grafting in irradiated tissues. Application of rVEGF may enable modulation of wound healing by influencing neovascularization. This could indicate a possible clinical approach for reducing fibrosis and chronic wound healing disorders in irradiated tissues. (C) 2003 Elsevier Inc.