Transgenic expression of leukemia inhibitory factor (LIF) blocksnormal vascular development but not pathological neovascularization inthe eye

[摘要] Purpose: Vascular development in the eye has been described as acomplex process involving both vasculogenesis and angiogenesis. Multiplecell types are involved in the process including angioblasts, vascularendothelial cells, astrocytes, pericytes, and Müller glial cells. Thissuggests that multiple growth factors and cytokines are required toregulate retinal vascular development. Leukemia inhibitory factor (LIF)is a member of the interleukin 6 family of cytokines. LIF is expressedduring inflammation and has been reported to affect vascular developmentin culture; however, its effects in vivo have not been demonstrated. Thepurpose of this study was to determine how LIF could regulate ocularvascular development.Methods: We have analyzed ocular vascular development in transgenicmice that express LIF in the ocular lens from embryonic day 11.Results: In transgenic mice, LIF reduced development of embryonicvasculature in the eye, and inhibited retinal vascular development.Inhibition in vivo was independent of vascular endothelial cell growthfactor (VEGF) expression. In older transgenic mice, the absence of aretinal vasculature resulted in retinal ischemia and elevated VEGFlevels. The upregulation of VEGF resulted in the proliferation ofpathological vascular membranes in the vitreous and neovascularizationpenetrating the retina, which in turn resulted in tractional retinaldetachment.Conclusions: LIF is a potent inhibitor of retinal vasculardevelopment. These transgenic mice will be useful as a model ofpersistent fetal vasculature and to study the mechanism for thedevelopment of neovascular membranes in the vitreous and could be usedto develop inhibitors of tractional detachment.

[学科分类] 生物化学/生物物理