FS145,一种含有WGD基序的蛋白质,先前是从跳蚤Xenopsilacheopis的唾液转录组中描述的。然而,其生物学功能和完整结构仍不确定。在这里,FS145被证实采用共同的αββ结构,其中WGD基序暴露在其表面上并且位于由残基72-81组成的环的正上方。此外,FS145剂量依赖性地抑制增殖,附着力,迁移,和HUVECs的管形成,不仅通过与整合素αvβ3结合,而且通过随后失活FAK/Src/MAPK途径以及减少MMP-2,MMP-9,VEGFA的表达,bFGF,Ang2,Tie2,HIF-1α,FAK。此外,FS145还抑制主动脉血管芽,并显示出强的抗血管生成活性,如离体评估,通过使用大鼠主动脉环检测,鸡胚尿囊膜,和斑马鱼胚胎模型。总之,我们的结果表明,FS145通过阻断整合素αvβ3来抑制离体和体外血管生成。目前的研究揭示了来自无脊椎动物的第一个具有WGD基序的抗血管生成的解整合素,并提供了抑制异常血管生成的有益药理活性。
FS145, a protein containing a WGD motif, was previously described from the salivary transcriptome of the flea Xenopsylla cheopis. Nevertheless, its biological function and complete structure are still uncertain. Herein, FS145 was confirmed to adopt a common αββ structure with the WGD motif exposed on its surface and located right at the top of a loop composed of residues 72-81. Furthermore, FS145 dose-dependently inhibited the proliferation, adhesion, migration, and tube formation of HUVECs by not only binding to integrin αvβ3 but also by subsequently inactivating the FAK/Src/MAPK pathway along with the reduction of the expression of MMP-2, MMP-9, VEGFA, bFGF, Ang2, Tie2, HIF-1α, and FAK. Moreover, FS145 also inhibited aortic vessel sprout and showed strong anti-angiogenic activities as assessed ex vivo, by employing the rat aortic ring assay, chick embryo chorioallantoic membrane, and zebrafish embryo models. Altogether, our results suggest that FS145 suppresses angiogenesis ex vivo and in vitro by blocking integrin αvβ3. The current study reveals the first anti-angiogenesis disintegrin with WGD motif from invertebrates and provides a beneficial pharmacological activity to inhibit abnormal angiogenesis.