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Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling

Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRβ-Cre mice with insulin receptor (Insr)...

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Autores principales: Warmke, Nele, Platt, Fiona, Bruns, Alexander F, Ozber, Claire H, Haywood, Natalie J, Abudushalamu, Yilizila, Slater, Charles, Palin, Victoria, Sukumar, Piruthivi, Wheatcroft, Stephen B, Yuldasheva, Nadira Y, Kearney, Mark T, Griffin, Kathryn J, Cubbon, Richard M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462386/
https://www.ncbi.nlm.nih.gov/pubmed/34460911
http://dx.doi.org/10.1210/endocr/bqab182
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author Warmke, Nele
Platt, Fiona
Bruns, Alexander F
Ozber, Claire H
Haywood, Natalie J
Abudushalamu, Yilizila
Slater, Charles
Palin, Victoria
Sukumar, Piruthivi
Wheatcroft, Stephen B
Yuldasheva, Nadira Y
Kearney, Mark T
Griffin, Kathryn J
Cubbon, Richard M
author_facet Warmke, Nele
Platt, Fiona
Bruns, Alexander F
Ozber, Claire H
Haywood, Natalie J
Abudushalamu, Yilizila
Slater, Charles
Palin, Victoria
Sukumar, Piruthivi
Wheatcroft, Stephen B
Yuldasheva, Nadira Y
Kearney, Mark T
Griffin, Kathryn J
Cubbon, Richard M
author_sort Warmke, Nele
collection PubMed
description Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRβ-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial plexi, and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the perivenous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.
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spelling pubmed-84623862021-09-27 Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling Warmke, Nele Platt, Fiona Bruns, Alexander F Ozber, Claire H Haywood, Natalie J Abudushalamu, Yilizila Slater, Charles Palin, Victoria Sukumar, Piruthivi Wheatcroft, Stephen B Yuldasheva, Nadira Y Kearney, Mark T Griffin, Kathryn J Cubbon, Richard M Endocrinology Research Article Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRβ-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial plexi, and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the perivenous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease. Oxford University Press 2021-08-30 /pmc/articles/PMC8462386/ /pubmed/34460911 http://dx.doi.org/10.1210/endocr/bqab182 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Warmke, Nele
Platt, Fiona
Bruns, Alexander F
Ozber, Claire H
Haywood, Natalie J
Abudushalamu, Yilizila
Slater, Charles
Palin, Victoria
Sukumar, Piruthivi
Wheatcroft, Stephen B
Yuldasheva, Nadira Y
Kearney, Mark T
Griffin, Kathryn J
Cubbon, Richard M
Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title_full Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title_fullStr Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title_full_unstemmed Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title_short Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling
title_sort pericyte insulin receptors modulate retinal vascular remodeling and endothelial angiopoietin signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462386/
https://www.ncbi.nlm.nih.gov/pubmed/34460911
http://dx.doi.org/10.1210/endocr/bqab182
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