Modulation of VEGF-Induced Retinal Vascular Permeability by Peroxisome Proliferator-Activated Receptor
| Autor: | John S. Penn, Colin A. Bretz, Sandra Suarez, Megan E. Capozzi, Rong Yang, Gary W. McCollum |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Vascular Endothelial Growth Factor A
MAPK/ERK pathway MAP Kinase Signaling System Peroxisome Proliferator-Activated Receptors Peroxisome proliferator-activated receptor Vascular permeability Thiophenes Biology Retina Capillary Permeability Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Claudin-1 Electric Impedance Animals Humans Claudin-5 Sulfones Extracellular Signal-Regulated MAP Kinases Receptor Cells Cultured chemistry.chemical_classification Analysis of Variance Cell Membrane Endothelial Cells Retinal Vessels Retinal Articles Immunohistochemistry Molecular biology Sensory Systems Mice Inbred C57BL Vascular endothelial growth factor Endothelial stem cell Ophthalmology Vascular endothelial growth factor A Receptors Vascular Endothelial Growth Factor chemistry Models Animal Immunology |
| Zdroj: | Investigative Ophthalmology & Visual Science. 55:8232-8240 |
| ISSN: | 0146-0404 |
| DOI: | 10.1167/iovs.14-14217 |
| Popis: | Purpose Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability. Methods Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 were assayed by Western blot analysis. Expression of VEGFR1 and R2 was measured by quantitative RT-PCR. Last, retinal vascular permeability was assayed in vivo by Evans blue extravasation. Results Human retinal microvascular endothelial cell monolayers treated with VEGF for 24 hours showed decreased TEER values that were completely reversed by the highest concentration of GSK0660 (10 μM) and PPARβ/δ-directed siRNA (20 μM). In HRMEC treated with VEGF, GSK0660 stabilized tight-junctions as evidenced by Claudin-1 staining, reduced phosphorylation of Erk1/2, and reduced VEGFR1/2 expression. Peroxisome proliferator-activated receptor β/δ siRNA had a similar effect on VEGFR expression and Claudin-1, supporting the specificity of GSK0660 in our experiments. Last, GSK0660 significantly inhibited VEGF-induced retinal vascular permeability and reduced retinal VEGFR1and R2 levels in C57BL/6 mice. Conclusions These data suggest a protective effect for PPARβ/δ antagonism against VEGF-induced vascular permeability, possibly through reduced VEGFR expression. Therefore, antagonism/reverse agonism of PPARβ/δ siRNA may represent a novel therapeutic methodology against retinal hyperpermeability and is worthy of future investigation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|