Abstract
Skin graft successful depends on reduction of local inflammation evoked by the surgical lesion and efficient neovascularization to nutrition the graft. It has been shown that N-terminal portion of the Annexin A1 protein (AnxA1) with its anti-inflammatory properties induces epithelial mucosa repair and presents potential therapeutic approaches. The role of AnxA1 on wound healing has not been explored and we investigated in this study the effect of the peptide Ac2–26 (N-terminal AnxA1 peptide Ac2–26; AnxA12–26) on heterologous skin scaffolds transplantation in BALB/c mice, focusing on inflammation and angiogenesis. Treatment with AnxA12–26, once a day, from day 3–60 after scaffold implantation improved the take of the implant, induced vessels formation, enhanced gene and protein levels of the vascular growth factor-A (VEGF-A) and fibroblast influx into allograft tissue. It also decreased pro- while increasing anti-inflammatory cytokines. The pro-angiogenic activity of AnxA12–26 was corroborated by topical application of AnxA12–26 on the subcutaneous tissue of mice. Moreover, treatment of human umbilical endothelial cells (HUVECs) with AnxA12–26 improved proliferation, shortened cycle, increased migration and actin polymerization similarly to those evoked by VEGF-A. The peptide treatment instead only potentiated the tube formation induced by VEGF-A. Collectively, our data showed that AnxA12–26 treatment favors the tissue regeneration after skin grafting by avoiding exacerbated inflammation and improving the angiogenesis process.
Highlights
Skin grafting has been employed to treat several acute and chronic wounds, and the success of the process is depending on an appropriated inflammatory reaction, neovascularization, granulation tissue formation, re-epithelialization, and tissue remodeling (Barrientos et al, 2008)
AnxA12−26 treatment induced augumentation on the number of vessels and migration of fibroblasts into the scaffold (Figures 1A–E), and enhanced the mRNA levels of mediators involved in the recovery of the transplanted tissue, as detected by greater levels of transforming growth factor-β1 (TGFβ1), myofibroblasts α smooth muscle actin (α-SMA), fibroblast growth factor basic (FGF-β) (Figures 1F–H), and mRNA and protein levels of VEGF-A (Figures 1I,J)
To assess if AnxA12−26 induces angiogenesis on absence of allograft transplantation, the dorsal skinfold chamber was implanted in mice and topical treatments started 3 days later
Summary
Skin grafting has been employed to treat several acute and chronic wounds, and the success of the process is depending on an appropriated inflammatory reaction, neovascularization, granulation tissue formation, re-epithelialization, and tissue remodeling (Barrientos et al, 2008). The N-terminal domain is unique to each member of the annexin superfamily, and it has been extensively shown that this region is responsible for the anti-inflammatory actions of AnxA1 (Perretti and Flower, 2004; Solito et al, 2006; Perretti and D’Acquisto, 2009). In this context, the N-terminal AnxA1 mimetic peptide Ac2–26 (AnxA12−26) inhibits neutrophil migration in inflammatory sites, epithelial cell proliferation, phagocytosis of apoptotic neutrophils by macrophages and neutrophil apoptosis, with especial role on the resolution of the inflammation (Gobbetti and Cooray, 2016). AnxA1 is able to interact to membrane phospholipids, the AnxA1 effects are dependent on phosphorylation and interaction with formyl– peptide receptors (FPR), especially FPR2, a G-protein coupled receptor; the peptide Ac2–26 is able to interact to both FPR1 and FPR2 (Cooray et al, 2013)
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