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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Acute local subcutaneous VEGF₁₆₅ injection for augmentation of skin flap viability: efficacy and mechanism

Departments of ²Surgery and ³Physiology, ¹Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8; and ⁴Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Submitted 3 March 2004 ; accepted in final form 16 June 2004

Distal skin ischemic necrosis is a common complication in skin flap surgery. The pathogenesis of skin flap ischemic necrosis is unclear, and there is no clinical treatment available. Here, we used the 4 x 10 cm rat dorsal skin flap model to test our hypothesis that subcutaneous injection of vascular endothelial growth factor 165 (VEGF₁₆₅) in skin flaps at the time of surgery is effective in augmentation of skin flap viability, which is associated with an increase in nitric oxide (NO) production, and the mechanism involves 1) an increase in skin flap blood flow in the early stage after surgery and 2) enhanced angiogenesis subsequently to sustain increased skin flap blood flow and viability. We observed that subcutaneous injection of VEGF₁₆₅ in skin flaps at the time of surgery increased skin flap viability in a dose-dependant manner. Subcutaneous injection of VEGF₁₆₅ at the dose of 2 µg/flap increased skin flap viability by 28% (P < 0.05; n = 8). Over 80% of this effect was blocked by intramuscular injection of the NO synthase (NOS) inhibitor N-nitro-L-arginine (13 mg/kg) 45 min before surgery (P < 0.05; n = 8). The VEGF₁₆₅ treatment also increased skin flap blood flow (2.68 ± 0.63 ml·min^–1·100 g^–1) compared with the control (1.26 ± 0.10 ml·min^–1·100 g^–1; P < 0.05, n = 6) assessed 6 h postoperatively. There was no change in skin flap capillary density at this time point. VEGF₁₆₅-induced increase in capillary density (32.2 ± 1.1 capillaries/mm²; P < 0.05, n = 7) compared with control (24.6 ± 1.4 capillaries/mm²) was seen 7 days postoperatively. There was also evidence to indicate that VEGF₁₆₅-induced NO production in skin flaps was stimulated by activation of NOS activity followed by upregulation of NOS protein expression. These observations support our hypothesis and for the first time provide an important insight into the mechanism of acute local VEGF₁₆₅ protein therapy in mitigation of skin flap ischemic necrosis.

rat skin flaps; ischemic necrosis; nitric oxide; vasorelaxation; angiogenesis; vascular endothelial growth factor

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