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Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells
BACKGROUND: Presenilin-1 (PS1) is a transmembrane protein first discovered because of its association with familial Alzheimer’s disease. Mice with null mutations in PS1 die shortly after birth exhibiting multiple CNS and non-CNS abnormalities. One of the most prominent features in the brains of PS1−...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556133/ https://www.ncbi.nlm.nih.gov/pubmed/23259730 http://dx.doi.org/10.1186/1471-2091-13-28 |
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author | De Gasperi, Rita Gama Sosa, Miguel A Elder, Gregory A |
author_facet | De Gasperi, Rita Gama Sosa, Miguel A Elder, Gregory A |
author_sort | De Gasperi, Rita |
collection | PubMed |
description | BACKGROUND: Presenilin-1 (PS1) is a transmembrane protein first discovered because of its association with familial Alzheimer’s disease. Mice with null mutations in PS1 die shortly after birth exhibiting multiple CNS and non-CNS abnormalities. One of the most prominent features in the brains of PS1−/− embryos is a vascular dysgenesis that leads to multiple intracerebral hemorrhages. The molecular and cellular basis for the vascular dysgenesis in PS1−/− mice remains incompletely understood. Because the extracellular matrix plays key roles in vascular development we hypothesized that an abnormal extracellular matrix might be present in endothelial cells lacking PS1 and examined whether the lack of PS1 affects expression of fibronectin a component of the extracellular matrix known to be essential for vascular development. RESULTS: We report that primary as well as continuously passaged PS1−/− endothelial cells contain more fibronectin than wild type cells and that the excess fibronectin in PS1−/− endothelial cells is incorporated into a fibrillar network. Supporting the in vivo relevance of this observation fibronectin expression was increased in microvascular preparations isolated from E14.5 to E18.5 PS1−/− embryonic brain. Reintroduction of PS1 into PS1−/− endothelial cells led to a progressive decrease in fibronectin levels showing that the increased fibronectin in PS1−/− endothelial cells was due to loss of PS1. Increases in fibronectin protein in PS1−/− endothelial cells could not be explained by increased levels of fibronectin RNA nor based on metabolic labeling studies by increased protein synthesis. Rather we show based on the rate of turnover of exogenously added biotinylated fibronectin that increased fibronectin in PS1−/− endothelial cells results from a slower degradation of the fibronectin fibrillar matrix on the cell surface. CONCLUSIONS: These studies show that PS1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells. These studies provide molecular clues that may help to explain the origin of the vascular dysgenesis that develops in PS1−/− embryonic mice. |
format | Online Article Text |
id | pubmed-3556133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35561332013-01-31 Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells De Gasperi, Rita Gama Sosa, Miguel A Elder, Gregory A BMC Biochem Research Article BACKGROUND: Presenilin-1 (PS1) is a transmembrane protein first discovered because of its association with familial Alzheimer’s disease. Mice with null mutations in PS1 die shortly after birth exhibiting multiple CNS and non-CNS abnormalities. One of the most prominent features in the brains of PS1−/− embryos is a vascular dysgenesis that leads to multiple intracerebral hemorrhages. The molecular and cellular basis for the vascular dysgenesis in PS1−/− mice remains incompletely understood. Because the extracellular matrix plays key roles in vascular development we hypothesized that an abnormal extracellular matrix might be present in endothelial cells lacking PS1 and examined whether the lack of PS1 affects expression of fibronectin a component of the extracellular matrix known to be essential for vascular development. RESULTS: We report that primary as well as continuously passaged PS1−/− endothelial cells contain more fibronectin than wild type cells and that the excess fibronectin in PS1−/− endothelial cells is incorporated into a fibrillar network. Supporting the in vivo relevance of this observation fibronectin expression was increased in microvascular preparations isolated from E14.5 to E18.5 PS1−/− embryonic brain. Reintroduction of PS1 into PS1−/− endothelial cells led to a progressive decrease in fibronectin levels showing that the increased fibronectin in PS1−/− endothelial cells was due to loss of PS1. Increases in fibronectin protein in PS1−/− endothelial cells could not be explained by increased levels of fibronectin RNA nor based on metabolic labeling studies by increased protein synthesis. Rather we show based on the rate of turnover of exogenously added biotinylated fibronectin that increased fibronectin in PS1−/− endothelial cells results from a slower degradation of the fibronectin fibrillar matrix on the cell surface. CONCLUSIONS: These studies show that PS1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells. These studies provide molecular clues that may help to explain the origin of the vascular dysgenesis that develops in PS1−/− embryonic mice. BioMed Central 2012-12-21 /pmc/articles/PMC3556133/ /pubmed/23259730 http://dx.doi.org/10.1186/1471-2091-13-28 Text en Copyright ©2012 De Gasperi et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article De Gasperi, Rita Gama Sosa, Miguel A Elder, Gregory A Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title | Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title_full | Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title_fullStr | Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title_full_unstemmed | Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title_short | Presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
title_sort | presenilin-1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556133/ https://www.ncbi.nlm.nih.gov/pubmed/23259730 http://dx.doi.org/10.1186/1471-2091-13-28 |
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