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

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.

Donepezil promotes skin flap survival through activation of the HIF‐1α/VEGF signalling pathway

“…Rivastigmine has the potential to enhance flap viability by activating the HIF-1α/VEGF signalling pathway. 4 The Western blot results in the present study revealed higher levels of both HIF-1α and VEGF in the experimental groups than in the control group. Together, these results demonstrate that donepezil may enhance flap survival through activation of the HIF-1α/VEGF signalling pathway.…”

“…Upon activation, VEGF assumes a pivotal role in angiogenesis through its binding to VEGF receptor 1, a high‐affinity tyrosine kinase receptor for VEGF, on the cell surface 22 . Rivastigmine has the potential to enhance flap viability by activating the HIF‐1α/VEGF signalling pathway 4 . The Western blot results in the present study revealed higher levels of both HIF‐1α and VEGF in the experimental groups than in the control group.…”

“…Nonetheless, they frequently undergo a cascade of pathological and physiological reactions postoperatively such as vascular spasms, thrombus formation, extensive neutrophil infiltration, apoptosis activation, and autophagy inhibition. These factors often culminate in partial or even complete flap necrosis 3,4 . These limitations have significantly curtailed their broad clinical use.…”

Identification of target genes in recurrent implantation failure women associated with maternal-fetal immune

“…IL-18 is a pro-in ammatory cytokine which promotes Th1 and Th17 cell differentiation and involvement in immune responses [27,28]. Besides that, IL-18 is also an angiogenesis mediator that induces endothelial cell tube formation in vitro and in vivo [29,30]. As previously con rmed that immune cells in maternal-fetal interface played an important role during embryo implantation.…”

Preliminary discussions about myocardial injury and rehabilitation

“…Soluble rhct-1 was obtained by renaturation; it has significant biological activity to promote the survival of damaged cardiomyocytes in vitro (29). SAB may regulate pkd1-hif-1 α-VEGF pathway and promote angiogenesis of myocardial tissue after myocardial infarction in rats (40). The expression of SDF-1 and crcr4 in the injured tissue was upregulated, and the cardiac function was improved after local injection of hypoxic preconditioning MSCs or MSCs into the AMI area of SD rats The upregulation of SDF-1/crcr4 axis in the myocardial infarction area may be one of the important ways to improve cardiac function after hypoxic preconditioning MSCs or MSCs transplantation (41).…”