دورية أكاديمية
Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization.
| العنوان: | Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization. |
|---|---|
| المؤلفون: | Zhang H; Department of Pediatrics and Neonatal-Perinatal Medicine, Augusta University, Augusta, Georgia, United States.; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Hudson FZ; Department of Pediatrics and Neonatal-Perinatal Medicine, Augusta University, Augusta, Georgia, United States.; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Xu Z; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Tritz R; Department of Pediatrics and Neonatal-Perinatal Medicine, Augusta University, Augusta, Georgia, United States.; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Rojas M; Vascular Biology Center, Augusta University, Augusta, Georgia, United States.; Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia, United States., Patel C; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Haigh SB; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Bordán Z; Vascular Biology Center, Augusta University, Augusta, Georgia, United States., Ingram DA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States.; Department of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States., Fulton DJ; Vascular Biology Center, Augusta University, Augusta, Georgia, United States.; Department of Pharmacology and Toxicology, Augusta University, Augusta, Georgia, United States., Weintraub NL; Vascular Biology Center, Augusta University, Augusta, Georgia, United States.; Department of Cardiology, Augusta University, Augusta, Georgia, United States., Caldwell RB; Vascular Biology Center, Augusta University, Augusta, Georgia, United States.; Vision Discovery Institute, Augusta University, Augusta, Georgia, United States.; Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States.; Charlie Norwood VA Medical Center, Augusta, Georgia, United States., Stansfield BK; Department of Pediatrics and Neonatal-Perinatal Medicine, Augusta University, Augusta, Georgia, United States.; Vascular Biology Center, Augusta University, Augusta, Georgia, United States.; Vision Discovery Institute, Augusta University, Augusta, Georgia, United States. |
| المصدر: | Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2018 May 01; Vol. 59 (6), pp. 2520-2528. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Association For Research In Vision And Ophthalmology (Arvo) Country of Publication: United States NLM ID: 7703701 Publication Model: Print Cited Medium: Internet ISSN: 1552-5783 (Electronic) Linking ISSN: 01460404 NLM ISO Abbreviation: Invest Ophthalmol Vis Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Brookline Ma : Association For Research In Vision And Ophthalmology (Arvo) Original Publication: St. Louis, Mosby. |
| مواضيع طبية MeSH: | Cell Proliferation*, Endothelial Cells/*pathology , Neurofibromin 1/*deficiency , Retinal Neovascularization/*etiology , Retinopathy of Prematurity/*etiology, Animals ; Aorta, Thoracic/pathology ; Cell Movement/physiology ; Endothelial Cells/metabolism ; Gene Silencing/physiology ; Humans ; Hypoxia/complications ; Mice ; Mice, Inbred C57BL ; Oxygen/toxicity ; Retinal Neovascularization/physiopathology ; Retinal Vessels/pathology ; Retinopathy of Prematurity/physiopathology ; Signal Transduction/physiology ; Vascular Endothelial Growth Factor A/pharmacology |
| مستخلص: | Purpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. Methods: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/-), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. Results: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/- retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/- and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/- retinas. Conclusions: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial. |
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| معلومات مُعتمدة: | R01 HL126949 United States HL NHLBI NIH HHS; R01 HL125926 United States HL NHLBI NIH HHS; R01 EY011766 United States EY NEI NIH HHS; I01 BX001233 United States BX BLRD VA; R01 AR070029 United States AR NIAMS NIH HHS |
| المشرفين على المادة: | 0 (Neurofibromin 1) 0 (Vascular Endothelial Growth Factor A) S88TT14065 (Oxygen) |
| تواريخ الأحداث: | Date Created: 20180531 Date Completed: 20190220 Latest Revision: 20190320 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5963003 |
| DOI: | 10.1167/iovs.17-22588 |
| PMID: | 29847659 |
| قاعدة البيانات: | MEDLINE |
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