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

Erine H Budi; Ons Mamai; Steven Hoffman; Rosemary J Akhurst; Rik Derynck

doi:10.1016/j.isci.2018.12.038

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

iScience. 2019 Jan 25:11:474-491. doi: 10.1016/j.isci.2018.12.038. Epub 2019 Jan 3.

Authors

Erine H Budi¹, Ons Mamai², Steven Hoffman¹, Rosemary J Akhurst³, Rik Derynck⁴

Affiliations

¹ Department 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, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA.
³ 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.
⁴ Department 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. Electronic address: rik.derynck@ucsf.edu.

Abstract

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.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Molecular Biology; Molecular Mechanism of Behavior.

Abstract

Grants and funding