title: Role of growth factors in improved skin flap viability caused by phosphodiesterase-5 inhibitor.
abstract: Flap necrosis is one of the major complications of reconstructive surgery and sildenafil citrate has been shown to decrease flap necrosis in preclinical animal models. However, the mechanisms underlying sildenafil's therapeutic efficacy are not known. As with other phosphodiesterase 5 selective inhibitors, sildenafil causes vasodilation and enhanced blood flow. In addition, sildenafil can also alter gene expression. This study is designed to test the hypothesis that increased expression of angiogenic growth factors may be responsible for therapeutic efficacy of sildenafil. A modified McFarlane flap measuring 3 x 10 cm was created on the dorsal skin of male Sprague-Dawley rats. For growth factor expression experiment, rats were administered either vehicle or sildenafil 10 mg/Kg intraperitoneal (IP). Ribonucleic acid (RNA) extracted from skin flap was analyzed to assess the messenger ribonucleic acid (mRNA) levels of different angiogenic growth factors. For skin flap viability experiment, fibrin film impregnated with vehicle, fibroblast growth factor (FGF) (5.0 microg) or vascular endothelial growth factor (VEGF) (2.0 microg) was applied to the wound. The skin flap was then returned to its native position and stapled in place. Total affected area (area of necrosis and blood flow stasis) of each rat on postoperative day 14 was analyzed with orthogonal polarization spectral imaging. Daily systemic treatment with sildenafil significantly (P < 0.05) increased the expression of FGF1 and FGF Receptor 3 on postoperative day 3 by 5.08- and 4.78-fold, respectively. In addition, sildenafil increased the expression of VEGF-A, VEGF-B, and VEGF-C by 2.66-, 2.02-, and 2.00-fold, respectively. Subcutaneous treatment with FGF but not VEGF-A tended to decrease total affected area in rats. These data demonstrate that sildenafil altered the expression of FGF and VEGF. Altered expression of growth factors may be, at least partly, responsible for the beneficial effects of sildenafil citrate on skin viability.
authors.affiliation: Department of Surgery, Dwight D. Eisenhower Army Medical Center, 300 Hospital Road, Augusta, Georgia 30905, USA. Bradley.Bandera@amedd.army.mil
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Bandera
authors.forename: Thach
authors.initials: T
authors.lastname: Pham
authors.forename: Crystal
authors.initials: C
authors.lastname: Hill-Pryor
authors.forename: Mariama
authors.initials: M
authors.lastname: Bah-Sow
authors.forename: Nelson
authors.initials: N
authors.lastname: Franco
authors.forename: Balakrishna M
authors.initials: BM
authors.lastname: Prasad
authors.forename: Jose
authors.initials: J
authors.lastname: Pizarro
mesh_terms: D000818:Animals; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D013524:Surgical Flaps / Q000098:blood supply* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D042561:Vascular Endothelial Growth Factor B / Q000187:drug effects / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000187:drug effects / Q000378:metabolism
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; C467498:vascular endothelial growth factor A, rat; D016220:Fibroblast Growth Factor 1; D000068677:Sildenafil Citrate