Pigment epithelium‐derived factor acts as an opponent of growth‐stimulatory factors in retinal glial–endothelial cell interactions

Abstract

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.

Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration Arrest

“…Because the ERK1/2 cascade is known to induce survival in various cells (40), the molecular mechanisms that prevent such an effect in ECs treated with PEDF constructs are not clear but may be dependent on the decline of ERK1/2 phosphorylation before JNK1/2 and p38␣ reach their peak of activity. PEDF-induced ERK1/2 phosphorylation has been previously reported by us (18) and others that linked it to the cytoprotective properties of PEDF (41,42). Indeed, our previous report showed that WT-PEDF and EEE-PEDF exhibit the same degree of neurotrophic and neuroprotective activity (18).…”

“…Modulation of MAPK signaling module by PEDF has been also suggested to play an important role in its physiological activities (44). PEDF-induced ERK1/2 phosphorylation has been largely implicated in the prosurvival effects of PEDF toward neural cells (41,42). On the other hand, the ability of PEDF to block growth of ECs and to reduce angiogenesis has been associated with up-regulation of p38 and JNK MAPKs (45,46) and p38-dependent cleavage of multiple caspases (47).…”

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

“…45,62,63 PEDF can protect RGC from death after glutamate toxicity, ischemia, trophic factor withdrawal, and in mouse models of glaucoma and inherited retinal degeneration. 35,38,[64][65][66][67] In vitro and in vivo, optimal RGC neuroprotective dosages of PEDF were 2.5 3 10 À5 lg/lL and 1 lg/lL, respectively. Others report that in vivo, 0.001 lg/lL is required to protect RGC from excitotoxicity and serum withdrawal, 36 a concentration of PEDF that is also neuroprotective for photoreceptors, cerebellar granule cells, and hippocampal neurons.…”

Retinal Vein Occlusion Induced by a MEK Inhibitor - Impact of Oxidative Stress on the Blood-Retinal Barrier

“…Under physiological conditions, Müller cells contribute to the integrity of the BRB; however, when exposed to cellular stress they impair the barrier function. Under normoxia, Müller cells secrete pigment epithelium-derived factor (PEDF), www.intechopen.com which downregulates VEGF expression and decreases vascular permeability (Yafai et al, 2007). Under hypoxia (Kaur et al, 2008) and oxidative stress ), PEDF expression is decreased in Müller cells, thus favoring the secretion of VEGF and breakdown of the inner BRB.…”

“…The presence of ROS could also induce the expression of the vascular permeability factor VEGF in endothelial cells (Chua et al, 1998;El-Remessy et al, 2003), often associated with downstream MAPK activation (Yang et al, 2010a;Zheng et al, 2010). In Müller cells, oxidative stress leads to decreased PEDF expression , thus relieving its antagonistic effect on VEGF action and subsequent MAPK activation in endothelial cells (Yafai et al, 2007), contributing to increased vascular permeability and breakdown of the inner BRB.…”