Prolonged blockade of VEGF receptors does not damage retinal photoreceptors or ganglion cells.

Abstract

It has recently been reported that relatively short-term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF-induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow-up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition-related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 microg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild-type mice given periocular injections of 5 microg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases.

• Authors: Akiko Miki, Katsuaki Miki, Shinji Ueno, Delphine M Bonnet Wersinger, Cynthia Berlinicke, Gillian C Shaw, Shinichi Usui, Yuxia Wang, Donald J Zack, Peter A Campochiaro
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 224 Issue 1 Pg. 262-72 (Jul 2010) ISSN: 1097-4652 [Electronic] United States
• PMID: 20232317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2010 Wiley-Liss, Inc.

Chemical References

• 3-(4-dimethylaminobenzylidene)-1,3-dihydroindol-2-one
• Angiogenesis Inhibitors
• Indoles
• Protein Kinase Inhibitors
• Vascular Endothelial Growth Factor A
• Receptors, Vascular Endothelial Growth Factor
• Proto-Oncogene Proteins c-akt

Topics

• Angiogenesis Inhibitors (administration & dosage, toxicity)
• Animals
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Electroretinography
• Indoles (administration & dosage, toxicity)
• Injections
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Phosphorylation
• Photoreceptor Cells, Vertebrate (drug effects, metabolism, pathology)
• Protein Kinase Inhibitors (administration & dosage, toxicity)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, genetics, metabolism)
• Retinal Ganglion Cells (drug effects, metabolism, pathology)
• Retinal Neovascularization (genetics, metabolism, pathology, prevention & control)
• Signal Transduction (drug effects)
• Time Factors
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, metabolism)