Pigment epithelium-derived factor (PEDF), a
glycoprotein with pleiotropic functions, is naturally occuring in the eye and considered as crucial to prevent
pathological angiogenesis. Since
retinal glial (Müller) cells produce PEDF, the authors have studied its impact on glial-endothelial cellular interactions. Bovine
retinal endothelial cells were cultured in the presence of
culture media originating from primary Müller cells, and endothelial proliferation as well as phosphorylation of the
mitogen-activated protein kinases extracellular signal-regulated kinases (ERK)-1/-2 were investigated. The concerted activity of Müller-cell derived soluble mediators attenuated endothelial proliferation and ERK-1/-2 activation, regardless of whether the Müller cells were preincubated under normoxia or
hypoxia, and even though the endothelial cells were stimulated by
vascular endothelial growth factor-A (
VEGF). This inhibitory activity was no longer demonstrable if high levels of
basic fibroblast growth factor or
VEGF were supplied, suggesting that in cases of
pathological neovascularization, overproduction of proangiogenic mediators overrides the "antiangiogenic background" provided by Müller cells. However, neutralizing the activity of PEDF partially restored endothelial cell proliferation and resulted in increased ERK-1/-2 activation, which is in concordance with findings demonstrating that exogenously applied PEDF is able to suppress
VEGF-induced ERK-1/-2 phosphorylation. PEDF production by Müller cells is not only regulated by
retinal oxygen but also by the activity of soluble factors released from
retinal endothelial cells. For instance, PEDF levels were significantly elevated in glial (Müller)-endothelial cell cocultures as compared with bovine
retinal endothelial cell-free Müller cell cultures. These results have implications for the pathogenesis of
retinal neovascularization since the Müller cell may be regarded as a central control
element which modulates
retinal PEDF levels and, thus, is of critical importance for adjusting the balance between proangiogenic and antiangiogenic mediators.