Integration of TGF-β-induced Smad signaling in the insulin-induced transcriptional response in endothelial cells

Insulin signaling governs many processes including glucose homeostasis and metabolism, and is therapeutically used to treat hyperglycemia in diabetes. We demonstrated that insulin-induced Akt activation enhances the sensitivity to TGF-beta by directing an increase in cell surface TGF-beta receptors from a pool of intracellular TGF-beta receptors. Consequently, increased autocrine TGF-beta signaling in response to insulin participates in insulin-induced angiogenic responses of endothelial cells. With TGF-beta signaling controlling many cell responses, including differentiation and extracellular matrix deposition, and pathologically promoting fibrosis and cancer cell dissemination, we addressed to which extent autocrine TGF-beta signaling participates in insulin-induced gene responses of human endothelial cells. Transcriptome analyses of the insulin response, in the absence or presence of a TGF-beta receptor kinase inhibitor, revealed substantial positive and negative contributions of autocrine TGF-beta signaling in insulin-responsive gene responses. Furthermore, insulin-induced responses of many genes depended on or resulted from autocrine TGF-beta signaling. Our analyses also highlight extensive contributions of autocrine TGF-beta signaling to basal gene expression in the absence of insulin, and identified many novel TGF-beta-responsive genes. This data resource may aid in the appreciation of the roles of autocrine TGF-beta signaling in normal physiological responses to insulin, and implications of therapeutic insulin usage.