Rivastigmine Regulates the HIF-1α/VEGF Signaling Pathway to Induce Angiogenesis and Improves the Survival of Random Flaps in Rats.

Yingying Liu,Jibing He,Wenjie Li,Xinyi Ma,Dingsheng Lin,Yi Lin

doi:10.3389/fphar.2021.818907

Abstract

Random skin flaps are frequently used to repair skin damage. However, the ischemic and hypoxic necrosis limits their wider application. Rivastigmine, a carbamate cholinesterase inhibitor (ChEI), has also been shown to reduce ischemia–reperfusion injury (IRI) and inflammation. This study was performed to examine the effect of rivastigmine on flap survival. Sixty male Sprague–Dawley rats with a modified McFarland flap were randomly divided into three groups: control group, 1 ml of solvent (10% DMSO + 90% corn oil); low-dose rivastigmine group (Riv-L), 1.0 mg/kg; and high-dose rivastigmine group (Riv-H), 2.0 mg/kg. All rats were treated once a day. On day 7, the skin flap survival area was measured. After staining with hematoxylin and eosin (H&E), the pathological changes and microvessel density (MVD) were examined. The expression of inflammatory factors IL-1β and IL-18, CD34, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. The malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were examined to determine the degree of oxidative stress. Lead oxide/gelatin angiography showed neovascularization and laser Doppler blood flowmetry showed the blood filling volume. Rivastigmine significantly increased the flap survival area and improved neovascularization. CD34, VEGF, and HIF-1α expression were increased, These changes were more pronounced in the Riv-H group. Treatment with rivastigmine reduced the level of MDA, improved SOD activity, and reduced expression of IL-1β and IL-18. Our results indicate that Rivastigmine can increase angiogenesis and significantly improve flap survival.

Highlights

Skin flaps are widely used for plastic surgery, burns and other applications to repair skin defects caused by tumor resection, trauma, ulcers, large pressure sores, etc., and restore function, correct deformities, and improve appearance(Dehdashtian et al, 2019).There is increasing interest in the function and esthetics of skin flaps for treatment of skin defects(Kushida-Contreras et al, 2021)
Necrosis of the distal flap tissue progressed after completion of the operation, and there was a very clear boundary between the necrotic and surviving areas on day 7
We found that the effects of rivastigmine on angiogenesis and blood circulation seem to be related to the regulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF)

Summary

Introduction

Skin flaps are widely used for plastic surgery, burns and other applications to repair skin defects caused by tumor resection, trauma, ulcers, large pressure sores, etc., and restore function, correct deformities, and improve appearance(Dehdashtian et al, 2019).There is increasing interest in the function and esthetics of skin flaps for treatment of skin defects(Kushida-Contreras et al, 2021). The size of the available flaps mainly depends on the capillary vascular resistance and perfusion pressure (El Shaer et al, 2019). Partial or complete avascular necrosis during flap transplantation is a major problem (Zahir et al, 1998). Based on their histological characteristics, random flaps have a maximum aspect ratio of 1.5–2:1. The skin flap survival area can be increased by increasing blood perfusion and constructing a new capillary network. Inhibition of oxidative stress, inflammation, and pyrolysis can improve the skin flap survival area (Fang et al, 2020)

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