Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway

Abstract

Growth arrest-specific protein 6 (Gas6) induces the activation of Axl receptor tyrosine kinase (Axl), which plays an important role in angiogenic processes, including proliferation, migration, invasion, tube formation and pericyte recruitment of endothelial cells. The inhibition of Gas6/Axl pathway has been demonstrated to be an effective anti-angiogenic therapy. Luteolin, which is a natural active flavonoid, has been reported to possess anti-angiogenic effects. However, the underlying mechanism of luteolin in anti-angiogenesis is not fully understood. Herein, we report that luteolin significantly inhibited the Gas6-induced proliferation, migration, invasion and tube formation of human microvascular endothelial cells (HMEC‑1s) in vitro, and suppressed the Gas6-induced recruitment of human brain vascular pericytes (HBVPs) to the endothelial tubes. Luteolin also suppressed Gas6-induced microvessel sprouting in aortic ring assay and neovascularization in chick chorioallantoic membrane assay. The anti-angiogenic effect of luteolin may be associated with the inhibition of the Gas6/Axl pathway and its downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Taken together, the present study provides new evidence regarding an anti-angiogenic mechanism of luteolin, and supports the notion that the dietary intake of luteolin contributes to the treatment of pathological angiogenesis.

Halogenated Flavonoid Derivatives Display Antiangiogenic Activity

“…The parameters measured in this assay via the Angiogenesis Analyser plugin [ 40 ]; the number (nb) of junctions and meshes, number and length of master segments and segments offer high sensitivity in the detection of different features of angiogenesis [ 41 ]. As shown in Figure 2 , the reference standard luteolin showed around 30% decrease in tube formation, in agreement with previous reports [ 38 , 42 ]. In this regard, all of the evaluated derivatives demonstrated higher inhibition of tube formation than the active reference luteolin ( Figure 2 ).…”

Antiangiogenic Activity of Flavonoids: A Systematic Review and Meta-Analysis

“…The second and third sets, however, tested the antiangiogenic activity of flavonoids on CAMs with abnormal angiogenesis using either proangiogenic factors for set 2 (4 studies) or cancer cell lines for set 3 (9 studies). 10 studies [ 18 , 95 , 100 , 132 , 137 , 139 , 140 , 141 , 145 , 149 ] out of the 25 eligible studies were not included in any of the conducted meta-analyses as they failed to report the required data outcomes or did not fit under any particular subgroup.…”

The Effect of Five-Day Dry Immersion on the Nervous and Metabolic Mechanisms of the Circulatory System

“…AXL is expressed mainly in the vascular endothelium, and is involved in the regulation of proliferation, migration, invasion, and the formation of endothelial cells (Li et al, 2017). It was shown that Gas6/UFO signaling plays an important role in the survival of endothelial cells during the development of acidosis (Gustafsson et al, 2009).…”