title: The Eyes Absent Proteins in Developmental and Pathological Angiogenesis.
abstract: Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3 is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivo and in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of γ-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tadjuidje
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Ram Naresh
authors.initials: RN
authors.lastname: Pandey
authors.affiliation: Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: James A
authors.initials: JA
authors.lastname: Stefater
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: rashmi.hegde@cchmc.org.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000517:prevention & control; D010100:Oxygen / Q000009:adverse effects; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000139:chemically induced / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C466082:Eya3 protein, mouse; D017027:Protein Tyrosine Phosphatases; D010100:Oxygen