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

Angiogenesis, the development of new blood vessels, is a key process in disease. We reported that insulin promotes translocation of transforming growth factor beta (TGF-beta) receptors to the plasma membrane of epithelial and fibroblast cells, thus enhancing TGF-beta responsiveness. Since insulin promotes angiogenesis, we addressed whether increased autocrine TGF-beta signaling participates in endothelial cell responses to insulin. We show that insulin enhances TGF-beta responsiveness and autocrine TGF-beta signaling in primary human endothelial cells, by inducing a rapid increase in cell surface TGF-beta receptor levels. Autocrine TGF-beta/Smad signaling contributed substantially to insulin-induced gene expression associated with angiogenesis, including TGF-beta target genes encoding angiogenic mediators; was essential for endothelial cell migration; and participated in endothelial cell invasion and network formation. Blocking TGF-beta 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-beta signaling is integral to endothelial cell and angiogenic responses to insulin.