Abstract
Sodium butyrate (NaBu), a form of short-chain fatty acid (SCFA), acts classically as a potent anti-angiogenic agent in tumour angiogenesis models, some authors demonstrated that low concentrations of NaBu may contribute to healing of tendon-bone injury in part at least through promotion of tissue remodelling. Here, we investigated the effects of low-range concentrations of NaBu using in vitro and in vivo assays using angiogenesis as the primary outcome measure and the mechanisms through which it acts. We demonstrated that NaBu, alone or perfused from the UltraBraid+NaBu suture was pro-angiogenic at very low-range doses promoting migration, tube formation and cell invasion in bovine aortic endothelial cells (BAECs). Furthermore, cell exposure to low NaBu concentrations increased expression of proteins involved in angiogenic cell signalling, including p-PKCβ1, p-FAK, p-ERK1/2, p-NFκβ, p-PLCγ1 and p-VEGFR2. In addition, inhibitors of both VEGFR2 and PKCβ1 blocked the angiogenic response. In in vivo assays, low concentrations of NaBu induced neovascularization in sponge implants in mice, evidenced by increased numbers of vessels and haemoglobin content in these implants. The findings in this study indicate that low concentrations of NaBu could be an important compound to stimulate angiogenesis at a site where vasculature is deficient and healing is compromised.
Highlights
Sodium butyrate (NaBu), a form of short-chain fatty acid (SCFA), has been reported to exert profoundly effects on mammalian cells in vitro and modify the activity of many types of cells[1,2], such as colorectal cancer cells[3,4,5]
In vitro testing showed that addition of sodium butyrate between 25 ng/ml and 1ug/ml to bovine aortic endothelial cells (BAECs) in MatrigelTM gel caused a significant increase in tube-like-structure formation (Fig. 1)
Using the sponge implant model, we showed that sodium butyrate soaked sponges (0.1–1.0 μg/ml) demonstrated a notable increase in Hb influx (Fig. 7A,B,D), and the number of new microvessels within the matrix measured after 7 days (Fig. 7C), levels of vascular endothelial growth factor (VEGF) were not found to be elevated
Summary
Sodium butyrate (NaBu), a form of short-chain fatty acid (SCFA), has been reported to exert profoundly effects on mammalian cells in vitro and modify the activity of many types of cells[1,2], such as colorectal cancer cells[3,4,5]. It is recognized to serve as a major energy substrate for colonocytes, exert potent effects on epithelial cells, induce cell replication and proliferation, act as an inducer or inhibitor of cell differentiation, induce apoptosis[6,7,8,9], and lead to cell growth arrest or cell death[10,11]. It can modify cell morphology, possibly through its effects on the cytoskeleton[1,2,12]. Here, we aimed to investigate the mechanisms through which NaBu enhances tendon-bones injury via modulation of angiogenesis
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