Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization
| Autor: | David J. Fulton, Hanfang Zhang, Farlyn Z. Hudson, Brian K. Stansfield, Modesto Rojas, Rebekah Tritz, Chintan Patel, Zsuzsanna Bordan, Stephen Haigh, Zhimin Xu, David A. Ingram, Ruth B. Caldwell, Neal L. Weintraub |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A congenital hereditary and neonatal diseases and abnormalities genetic structures Aorta Thoracic Retinal Neovascularization Retina Neovascularization 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Movement medicine retinopathy of prematurity Animals Humans Gene Silencing Hypoxia Cell Proliferation Hyperoxia neurofibromatosis Neurofibromin 1 biology Chemistry Endothelial Cells Retinal Vessels Retinal medicine.disease VEGF eye diseases Cell biology nervous system diseases Endothelial stem cell Mice Inbred C57BL Oxygen Vascular endothelial growth factor A 030104 developmental biology medicine.anatomical_structure 030221 ophthalmology & optometry biology.protein endothelial cell sense organs medicine.symptom Retinopathy Ras Signal Transduction |
| Zdroj: | Investigative Ophthalmology & Visual Science |
| ISSN: | 1552-5783 0146-0404 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|