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Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation

Female hormones and sex-specific factors are established determinants of endothelial function, yet their relative contribution to human endothelium phenotypes has not been defined. Using human umbilical vein endothelial cells (HUVECs) genotyped by donor's sex, we investigated the influence of s...

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Autores principales: Boscaro, Carlotta, Trenti, Annalisa, Baggio, Chiara, Scapin, Chiara, Trevisi, Lucia, Cignarella, Andrea, Bolego, Chiara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773665/
https://www.ncbi.nlm.nih.gov/pubmed/33390959
http://dx.doi.org/10.3389/fphar.2020.587221
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author Boscaro, Carlotta
Trenti, Annalisa
Baggio, Chiara
Scapin, Chiara
Trevisi, Lucia
Cignarella, Andrea
Bolego, Chiara
author_facet Boscaro, Carlotta
Trenti, Annalisa
Baggio, Chiara
Scapin, Chiara
Trevisi, Lucia
Cignarella, Andrea
Bolego, Chiara
author_sort Boscaro, Carlotta
collection PubMed
description Female hormones and sex-specific factors are established determinants of endothelial function, yet their relative contribution to human endothelium phenotypes has not been defined. Using human umbilical vein endothelial cells (HUVECs) genotyped by donor's sex, we investigated the influence of sex and estrogenic agents on the main steps of the angiogenic process and on key proteins governing HUVEC metabolism and migratory properties. HUVECs from female donors (fHUVECs) showed increased viability (p < 0.01) and growth rate (p < 0.01) compared with those from males (mHUVECs). Despite higher levels of G-protein coupled estrogen receptor (GPER) in fHUVECs (p < 0.001), treatment with 17β-estradiol (E2) and the selective GPER agonist G1 (both 1–100 nM) did not affect HUVEC viability. Migration and tubularization in vitro under physiological conditions were higher in fHUVECs than in mHUVECs (p < 0.05). E2 treatment (1–100 nM) upregulated the glycolytic activator PFKFB3 with higher potency in fHUVECs than in mHUVECs, despite comparable baseline levels. Moreover, Y576/577 phosphorylation of focal adhesion kinase (FAK) was markedly enhanced in fHUVECs (p < 0.001), despite comparable Src activation levels. While the PI3K inhibitor LY294002 (25 µM) inhibited HUVEC migration (p < 0.05), Akt phosphorylation levels in fHUVECs and mHUVECs were comparable. Finally, digitoxin treatment, which inhibits Y576/577 FAK phosphorylation, abolished sexual dimorphism in HUVEC migration. These findings unravel complementary modulation of HUVEC functional phenotypes and signaling molecules involved in angiogenesis by hormone microenvironment and sex-specific factors, and highlight the need for sex-oriented pharmacological targeting of endothelial function.
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spelling pubmed-77736652021-01-01 Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation Boscaro, Carlotta Trenti, Annalisa Baggio, Chiara Scapin, Chiara Trevisi, Lucia Cignarella, Andrea Bolego, Chiara Front Pharmacol Pharmacology Female hormones and sex-specific factors are established determinants of endothelial function, yet their relative contribution to human endothelium phenotypes has not been defined. Using human umbilical vein endothelial cells (HUVECs) genotyped by donor's sex, we investigated the influence of sex and estrogenic agents on the main steps of the angiogenic process and on key proteins governing HUVEC metabolism and migratory properties. HUVECs from female donors (fHUVECs) showed increased viability (p < 0.01) and growth rate (p < 0.01) compared with those from males (mHUVECs). Despite higher levels of G-protein coupled estrogen receptor (GPER) in fHUVECs (p < 0.001), treatment with 17β-estradiol (E2) and the selective GPER agonist G1 (both 1–100 nM) did not affect HUVEC viability. Migration and tubularization in vitro under physiological conditions were higher in fHUVECs than in mHUVECs (p < 0.05). E2 treatment (1–100 nM) upregulated the glycolytic activator PFKFB3 with higher potency in fHUVECs than in mHUVECs, despite comparable baseline levels. Moreover, Y576/577 phosphorylation of focal adhesion kinase (FAK) was markedly enhanced in fHUVECs (p < 0.001), despite comparable Src activation levels. While the PI3K inhibitor LY294002 (25 µM) inhibited HUVEC migration (p < 0.05), Akt phosphorylation levels in fHUVECs and mHUVECs were comparable. Finally, digitoxin treatment, which inhibits Y576/577 FAK phosphorylation, abolished sexual dimorphism in HUVEC migration. These findings unravel complementary modulation of HUVEC functional phenotypes and signaling molecules involved in angiogenesis by hormone microenvironment and sex-specific factors, and highlight the need for sex-oriented pharmacological targeting of endothelial function. Frontiers Media S.A. 2020-12-17 /pmc/articles/PMC7773665/ /pubmed/33390959 http://dx.doi.org/10.3389/fphar.2020.587221 Text en Copyright © 2020 Boscaro, Trenti, Scapin, Baggio, Trevisi, Cignarella and Bolego http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Boscaro, Carlotta
Trenti, Annalisa
Baggio, Chiara
Scapin, Chiara
Trevisi, Lucia
Cignarella, Andrea
Bolego, Chiara
Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title_full Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title_fullStr Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title_full_unstemmed Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title_short Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
title_sort sex differences in the pro-angiogenic response of human endothelial cells: focus on pfkfb3 and fak activation
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773665/
https://www.ncbi.nlm.nih.gov/pubmed/33390959
http://dx.doi.org/10.3389/fphar.2020.587221
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