Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells

Summary: Angiogenesis, the development of new blood vessels, is a key process in disease. We reported that insulin promotes translocation of transforming growth factor β (TGF-β) receptors to the plasma membrane of epithelial and fibroblast cells, thus enhancing TGF-β responsiveness. Since insulin pr...

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Main Authors:	Erine H. Budi, Ons Mamai, Steven Hoffman, Rosemary J. Akhurst, Rik Derynck
Format:	Article
Language:	English
Published:	Elsevier 2019-01-01
Series:	iScience
Online Access:	http://www.sciencedirect.com/science/article/pii/S2589004218302682

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spelling	doaj-9e41c6dd15564952b7f29e1ffbb0bd142020-11-24T21:51:52ZengElsevieriScience2589-00422019-01-0111474491Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial CellsErine H. Budi0Ons Mamai1Steven Hoffman2Rosemary J. Akhurst3Rik Derynck4Department of Cell and Tissue Biology, University of California at San Francisco Broad Center, Room RMB-1027, 35 Medical Center Way, San Francisco, CA 94143-0669, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USAHelen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USADepartment of Cell and Tissue Biology, University of California at San Francisco Broad Center, Room RMB-1027, 35 Medical Center Way, San Francisco, CA 94143-0669, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USADepartment of Anatomy, University of California at San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USADepartment of Cell and Tissue Biology, University of California at San Francisco Broad Center, Room RMB-1027, 35 Medical Center Way, San Francisco, CA 94143-0669, USA; Department of Anatomy, University of California at San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA; Corresponding authorSummary: Angiogenesis, the development of new blood vessels, is a key process in disease. We reported that insulin promotes translocation of transforming growth factor β (TGF-β) receptors to the plasma membrane of epithelial and fibroblast cells, thus enhancing TGF-β responsiveness. Since insulin promotes angiogenesis, we addressed whether increased autocrine TGF-β signaling participates in endothelial cell responses to insulin. We show that insulin enhances TGF-β responsiveness and autocrine TGF-β signaling in primary human endothelial cells, by inducing a rapid increase in cell surface TGF-β receptor levels. Autocrine TGF-β/Smad signaling contributed substantially to insulin-induced gene expression associated with angiogenesis, including TGF-β target genes encoding angiogenic mediators; was essential for endothelial cell migration; and participated in endothelial cell invasion and network formation. Blocking TGF-β signaling impaired insulin-induced microvessel outgrowth from neonatal aortic rings and modified insulin-stimulated blood vessel formation in zebrafish. We conclude that enhanced autocrine TGF-β signaling is integral to endothelial cell and angiogenic responses to insulin. : Molecular Biology; Molecular Mechanism of Behavior; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Molecular Biology, Molecular Mechanism of Behavior, Cell Biology, Functional Aspects of Cell Biologyhttp://www.sciencedirect.com/science/article/pii/S2589004218302682
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Erine H. Budi Ons Mamai Steven Hoffman Rosemary J. Akhurst Rik Derynck
spellingShingle	Erine H. Budi Ons Mamai Steven Hoffman Rosemary J. Akhurst Rik Derynck Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells iScience
author_facet	Erine H. Budi Ons Mamai Steven Hoffman Rosemary J. Akhurst Rik Derynck
author_sort	Erine H. Budi
title	Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells
title_short	Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells
title_full	Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells
title_fullStr	Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells
title_full_unstemmed	Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells
title_sort	enhanced tgf-β signaling contributes to the insulin-induced angiogenic responses of endothelial cells
publisher	Elsevier
series	iScience
issn	2589-0042
publishDate	2019-01-01
description	Summary: Angiogenesis, the development of new blood vessels, is a key process in disease. We reported that insulin promotes translocation of transforming growth factor β (TGF-β) receptors to the plasma membrane of epithelial and fibroblast cells, thus enhancing TGF-β responsiveness. Since insulin promotes angiogenesis, we addressed whether increased autocrine TGF-β signaling participates in endothelial cell responses to insulin. We show that insulin enhances TGF-β responsiveness and autocrine TGF-β signaling in primary human endothelial cells, by inducing a rapid increase in cell surface TGF-β receptor levels. Autocrine TGF-β/Smad signaling contributed substantially to insulin-induced gene expression associated with angiogenesis, including TGF-β target genes encoding angiogenic mediators; was essential for endothelial cell migration; and participated in endothelial cell invasion and network formation. Blocking TGF-β signaling impaired insulin-induced microvessel outgrowth from neonatal aortic rings and modified insulin-stimulated blood vessel formation in zebrafish. We conclude that enhanced autocrine TGF-β signaling is integral to endothelial cell and angiogenic responses to insulin. : Molecular Biology; Molecular Mechanism of Behavior; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Molecular Biology, Molecular Mechanism of Behavior, Cell Biology, Functional Aspects of Cell Biology
url	http://www.sciencedirect.com/science/article/pii/S2589004218302682
work_keys_str_mv	AT erinehbudi enhancedtgfbsignalingcontributestotheinsulininducedangiogenicresponsesofendothelialcells AT onsmamai enhancedtgfbsignalingcontributestotheinsulininducedangiogenicresponsesofendothelialcells AT stevenhoffman enhancedtgfbsignalingcontributestotheinsulininducedangiogenicresponsesofendothelialcells AT rosemaryjakhurst enhancedtgfbsignalingcontributestotheinsulininducedangiogenicresponsesofendothelialcells AT rikderynck enhancedtgfbsignalingcontributestotheinsulininducedangiogenicresponsesofendothelialcells
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Enhanced TGF-β Signaling Contributes to the Insulin-Induced Angiogenic Responses of Endothelial Cells

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