Kaempferol prevents angiogenesis of rat intestinal microvascular endothelial cells induced by LPS and TNF-? via inhibiting VEGF/Akt/p38 signaling pathways and maintaining gut-vascular barrier integrity

Kaempferol is a major flavonoid found in natural plant extracts; it shows great potential in anti-inflammatory and anti-cancer medicine. However, the underlying mechanism of the protective action of kaempferol on the gutvascular barrier (GVB) and the active sites preventing intestinal micro-angiogenesis has not been reported. The purpose of our study is to investigate the protective effect of kaempferol on the barrier damage induced by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha), and its mechanism of protective action on intestinal micro-angiogenesis. Our data showed that the combination of LPS and TNF-alpha activates the inflammatory response of the rat intestinal microvascular endothelial cells (RIMVECs), leading to overexpression of vascular endothelial growth factors (VEGFs). Also, the permeability of GVB and transepithelial electrical resistance (TEER) constructed by Transwell and the tubular structure of RIMVEC were significantly affected. Kaempferol (25, 50, and 100 mu M) decreased the inflammatory factor secretion and GVB permeability, downregulated the expression of VEGFs, p-Akt, and hypoxia-inducible factor-1alpha (HIF-1 alpha). It also alleviated the abnormal expression of tight junction proteins (TJs). Moreover, kaempferol may prevents intestinal angiogenesis in the presence of Akt inhibitor (MK-2206 2HCl) by regulating tube formation and downstream signaling of the VEGF/Akt pathways. In addition, the wound healing test showed that kaempferol had a similar effect in the presence of p38 inhibitor (SB203580), which intuitively restrained the migration of RIMVECs and reduced the p38 MAPK signaling. Our results demonstrated that kaempferol exhibits significant anti-inflammatory effects in LPS and TNF-alpha induced inflammatory environments. Kaempferol prevents intestinal angiogenesis by impeding the tube formation and migration of RIMVECs. It also suppresses the expression of angiogenesis-related signals, thereby protecting the GVB.

Automated summary

In this study, the protective effect of kaempferol on the damage to the gutvascular barrier caused by LPS and TNF-alpha was investigated. Our results showed that kaempferol exhibited significant anti-inflammatory effects and prevented intestinal angiogenesis by regulating tube formation and migration of RIMVECs and suppressing the expression of angiogenesis-related signals.