Valproic acid enhances the viability of random pattern skin flaps: involvement of enhancing angiogenesis and inhibiting oxidative stress and apoptosis

Valproic acid enhances the viability of random pattern skin flaps: involvement of enhancing angiogenesis and inhibiting oxidative stress and apoptosis Hongqiang Wu,1–3,* Jian Ding,1–3,* Lei Wang,3 Jinti Lin,1–3 Shihen Li,1–3 Guangheng Xiang,1–3 Liangfu Jiang,1–3 Huazi Xu,1–3 Weiyang Gao,1–3 Kailiang Zhou1–3 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China; 3The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work Background: Random skin flaps are commonly applied during plastic surgery, but distal flap necrosis limits their clinical applications. Valproic acid (VPA), a histone deacetylase inhibitor and a traditional antiepileptic agent, may promote flap survival.Materials and methods: Sprague–Dawley rats were randomly divided into VPA-treated and control groups. All rats received VPA or saline by intraperitoneal injections once daily for 7 days after the modified McFarlane flap model was established. On postoperative day 7, flap survival, laser Doppler blood flow, and water content were examined for flap viability, hematoxylin and eosin staining (H&E), immunohistochemistry (IHC), and Western blot analysis, and the status of angiogenesis, apoptosis, and oxidative stress were detected in the ischemic flaps.Results: VPA increased the survival area, blood flow, and number of microvessels in skin flaps on postoperative day 7 and reduced edema. VPA promoted angiogenesis by enhancing vascular endothelial growth factor (VEGF) mRNA transcription and upregulating VEGF and cadherin 5 expression, inhibited apoptosis via reduction of caspase 3 cleavage, and relieved oxidative stress by increasing superoxide dismutase (SOD) and glutathione (GSH) levels and reducing the malondialdehyde (MDA) level.Conclusion: VPA promoted random skin flap survival by enhancing angiogenesis and inhibiting oxidative stress and apoptosis. Keywords: valproic acid, random skin flap, angiogenesis, oxidative stress, apoptosis