title: MEF2C ablation in endothelial cells reduces retinal vessel loss and suppresses pathologic retinal neovascularization in oxygen-induced retinopathy.
abstract: Ischemic retinopathies, including retinopathy of prematurity and diabetic retinopathy, are major causes of blindness. Both have two phases, vessel loss and consequent hypoxia-driven pathologic retinal neovascularization, yet relatively little is known about the transcription factors regulating these processes. Myocyte enhancer factor 2 (MEF2) C, a member of the MEF2 family of transcription factors that plays an important role in multiple developmental programs, including the cardiovascular system, seems to have a significant functional role in the vasculature. We, therefore, generated endothelial cell (EC)-specific MEF2C-deficient mice and explored the role of MEF2C in retinal vascularization during normal development and in a mouse model of oxygen-induced retinopathy. Ablation of MEF2C did not cause appreciable defects in normal retinal vascular development. However, MEF2C ablation in ECs suppressed vessel loss in oxygen-induced retinopathy and strongly promoted vascular regrowth, consequently reducing retinal avascularity. This finding was associated with suppression of pathologic retinal angiogenesis and blood-retinal barrier dysfunction. MEF2C knockdown in cultured retinal ECs using small-interfering RNAs rescued ECs from death and stimulated tube formation under stress conditions, confirming the endothelial-autonomous and antiangiogenic roles of MEF2C. HO-1 was induced by MEF2C knockdown in vitro and may play a role in the proangiogenic effect of MEF2C knockdown on retinal EC tube formation. Thus, MEF2C may play an antiangiogenic role in retinal ECs under stress conditions, and modulation of MEF2C may prevent pathologic retinal neovascularization.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.forename: Junsong
authors.initials: J
authors.lastname: Gong
authors.forename: Debasish
authors.initials: D
authors.lastname: Maiti
authors.forename: Linh
authors.initials: L
authors.lastname: Vong
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wu
authors.forename: John J
authors.initials: JJ
authors.lastname: Schwarz
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001813:Blood-Retinal Barrier / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D007231:Infant, Newborn; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen; D034741:RNA, Small Interfering / Q000235:genetics; D015861:Retinal Neovascularization / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D012178:Retinopathy of Prematurity / Q000473:pathology / Q000503:physiopathology*
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D034741:RNA, Small Interfering; D010100:Oxygen