Cargando…
17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells
Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenes...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742772/ https://www.ncbi.nlm.nih.gov/pubmed/23967210 http://dx.doi.org/10.1371/journal.pone.0071440 |
_version_ | 1782280409876267008 |
---|---|
author | Caliceti, Cristiana Aquila, Giorgio Pannella, Micaela Morelli, Marco Bruno Fortini, Cinzia Pinton, Paolo Bonora, Massimo Hrelia, Silvana Pannuti, Antonio Miele, Lucio Rizzo, Paola Ferrari, Roberto |
author_facet | Caliceti, Cristiana Aquila, Giorgio Pannella, Micaela Morelli, Marco Bruno Fortini, Cinzia Pinton, Paolo Bonora, Massimo Hrelia, Silvana Pannuti, Antonio Miele, Lucio Rizzo, Paola Ferrari, Roberto |
author_sort | Caliceti, Cristiana |
collection | PubMed |
description | Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenesis downstream of vascular endothelial growth factor A (VEGF-A). The goal of our study was to establish whether estrogens modulate Notch activity in endothelial cells and the possible consequences on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with 17β-estradiol (E2) and the effects on Notch signalling were evaluated. E2 increased Notch1 processing as indicated by i) decreased levels of Notch1 transmembrane subunit ii) increased amount of Notch1 in nuclei iii) unaffected level of mRNA. Similarly, E2 increased the levels of the active form of Notch4 without altering Notch4 mRNA. Conversely, protein and mRNA levels of Notch2 were both reduced suggesting transcriptional repression of Notch2 by E2. Under conditions where Notch was activated by upregulation of Delta-like ligand 4 (Dll4) following VEGF-A treatment, E2 caused a further increase of the active form of Notch1, of the number of cells with nuclear Notch1 and of Hey2 mRNA. Estrogen receptor antagonist ICI 182.780 antagonized these effects suggesting that E2 modulation of Notch1 is mediated by estrogen receptors. E2 treatment abolished the increase in endothelial cells sprouting caused by Notch inhibition in a tube formation assay on 3D Matrigel and in mouse aortic ring explants. In conclusion, E2 affects several Notch pathway components in HUVECs, leading to an activation of the VEGF-A-Dll4-Notch1 axis and to a modulation of vascular branching when Notch signalling is inhibited. These results contribute to our understanding of the molecular mechanisms of cardiovascular protection exerted by estrogens by uncovering a novel role of E2 in the Notch signalling-mediated modulation of angiogenesis. |
format | Online Article Text |
id | pubmed-3742772 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37427722013-08-21 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells Caliceti, Cristiana Aquila, Giorgio Pannella, Micaela Morelli, Marco Bruno Fortini, Cinzia Pinton, Paolo Bonora, Massimo Hrelia, Silvana Pannuti, Antonio Miele, Lucio Rizzo, Paola Ferrari, Roberto PLoS One Research Article Estrogens play a protective role in coronary artery disease. The mechanisms of action are still poorly understood, although a role for estrogens in stimulation of angiogenesis has been suggested. In several cell types, estrogens modulate the Notch pathway, which is involved in controlling angiogenesis downstream of vascular endothelial growth factor A (VEGF-A). The goal of our study was to establish whether estrogens modulate Notch activity in endothelial cells and the possible consequences on angiogenesis. Human umbilical vein endothelial cells (HUVECs) were treated with 17β-estradiol (E2) and the effects on Notch signalling were evaluated. E2 increased Notch1 processing as indicated by i) decreased levels of Notch1 transmembrane subunit ii) increased amount of Notch1 in nuclei iii) unaffected level of mRNA. Similarly, E2 increased the levels of the active form of Notch4 without altering Notch4 mRNA. Conversely, protein and mRNA levels of Notch2 were both reduced suggesting transcriptional repression of Notch2 by E2. Under conditions where Notch was activated by upregulation of Delta-like ligand 4 (Dll4) following VEGF-A treatment, E2 caused a further increase of the active form of Notch1, of the number of cells with nuclear Notch1 and of Hey2 mRNA. Estrogen receptor antagonist ICI 182.780 antagonized these effects suggesting that E2 modulation of Notch1 is mediated by estrogen receptors. E2 treatment abolished the increase in endothelial cells sprouting caused by Notch inhibition in a tube formation assay on 3D Matrigel and in mouse aortic ring explants. In conclusion, E2 affects several Notch pathway components in HUVECs, leading to an activation of the VEGF-A-Dll4-Notch1 axis and to a modulation of vascular branching when Notch signalling is inhibited. These results contribute to our understanding of the molecular mechanisms of cardiovascular protection exerted by estrogens by uncovering a novel role of E2 in the Notch signalling-mediated modulation of angiogenesis. Public Library of Science 2013-08-13 /pmc/articles/PMC3742772/ /pubmed/23967210 http://dx.doi.org/10.1371/journal.pone.0071440 Text en © 2013 Caliceti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Caliceti, Cristiana Aquila, Giorgio Pannella, Micaela Morelli, Marco Bruno Fortini, Cinzia Pinton, Paolo Bonora, Massimo Hrelia, Silvana Pannuti, Antonio Miele, Lucio Rizzo, Paola Ferrari, Roberto 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title | 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title_full | 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title_fullStr | 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title_full_unstemmed | 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title_short | 17β-Estradiol Enhances Signalling Mediated by VEGF-A-Delta-Like Ligand 4-Notch1 Axis in Human Endothelial Cells |
title_sort | 17β-estradiol enhances signalling mediated by vegf-a-delta-like ligand 4-notch1 axis in human endothelial cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742772/ https://www.ncbi.nlm.nih.gov/pubmed/23967210 http://dx.doi.org/10.1371/journal.pone.0071440 |
work_keys_str_mv | AT caliceticristiana 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT aquilagiorgio 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT pannellamicaela 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT morellimarcobruno 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT fortinicinzia 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT pintonpaolo 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT bonoramassimo 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT hreliasilvana 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT pannutiantonio 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT mielelucio 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT rizzopaola 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells AT ferrariroberto 17bestradiolenhancessignallingmediatedbyvegfadeltalikeligand4notch1axisinhumanendothelialcells |