Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site

Liu, Hua; Ren, Jian-Guo; Cooper, William L.; Hawkins, Charles E.; Cowan, Mitra; Tong, Peter C.Y.

doi:10.1073/pnas.0308342101

Cited by 122 publications

(80 citation statements)

References 43 publications

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“…3). In contrast, an equimolar amount of a 20-mer fragment of pigment epithelium-derived factor (amino acids 102-121), derived from a biologically active region of this molecule (25), was inactive.…”

Section: Resultsmentioning

confidence: 97%

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Brines¹,

Patel

Villa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

282

283

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Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the ␤ common receptor. In the present work, we have delimited tissueprotective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58 -82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.cognition ͉ cytoprotection ͉ excitotoxicity ͉ ischemia-reperfusion injury ͉ wound healing

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Section: Resultsmentioning

confidence: 97%

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Brines¹,

Patel

Villa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

282

283

View full text Add to dashboard Cite

show abstract

“…PEDF is a major endogenous angiogenic inhibitor in the retina. Moreover, PEDF has recently been identified as a potent anti-inflammatory factor and anti-permeability factor (Liu et al 2004, Zhang et al 2005a. Furthermore, a decrease in ocular PEDF levels is believed to contribute to the pathogenesis of DR.…”

Section: Discussionmentioning

confidence: 99%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

229

152

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It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Mü ller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Mü ller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Mü ller cells, suggesting a VEGF receptormediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.

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“…PEDF counteracts VEGF-induced vascular hyperpermeability and inhibits endothelial cell migration toward a variety of angiogenic inducers including platelet-derived growth factor, VEGF, IL-8, acidic FGF, and lysophosphatidic acid. 34,35 VEGF exacerbates degradation of occludin and zona occludens-1 in vitro, and the loss of these proteins increases BBB leakage in the human brain. 36 Of the three proposed mechanisms underlying angiogenesis, such as sprouting, intussusception, and recruitment of endothelial progenitor cells, VEGF-induced sprouting mediated through VEGF receptor-2 is invariably accompanied by increased permeability.…”

Section: Effect Of Epidermal Growth Factor and Pigment Epitheliumderimentioning

confidence: 99%

Neurovascular Protection by Targeting Early Blood–Brain Barrier Disruption with Neurotrophic Factors after Ischemia–Reperfusion in Rats

Pillai

Shanbhag

Dittmar³

et al. 2013

J Cereb Blood Flow Metab

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The 'new penumbra' concept imbues the transition between injury and repair at the neurovascular unit with profound implications for selecting the appropriate type and timing of neuroprotective interventions. In this conceptual study, we investigated the protective effects of pigment epithelium-derived factor (PEDF) and compared them with the properties of epidermal growth factor (EGF) in a rat model of ischemia-reperfusion injury. We initiated a delayed intervention 3 hours after reperfusion using equimolar amounts of PEDF and EGF. These agents were then administered intravenously for 4 hours following reperfusion after 1 hour of focal ischemia. Magnetic resonance imaging indices were characterized, and imaging was performed at multiple time points post reperfusion. PEDF and EGF reduced lesion volumes at all time points as observed on T 2 -weighted images (T 2 -LVs). In addition PEDF selectively attenuated lesion volume expansion at 48 hours after reperfusion and persistently modulated blood-brain barrier (BBB) permeability at all time points. Intervention with peptides is suspected to cause edema formation at distant regions. The observed T 2 -LV reduction and BBB modulation by these trophic factors is probably mediated through a number of diverse mechanisms. A thorough evaluation of neurotrophins is still necessary to determine their time-dependent contributions against injury and their modulatory effects on repair after stroke.

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Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site

Cited by 122 publications

References 43 publications

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Neurovascular Protection by Targeting Early Blood–Brain Barrier Disruption with Neurotrophic Factors after Ischemia–Reperfusion in Rats

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