Journal Article

Thrombospondin-4 mediates TGF-β-induced angiogenesis

Muppala, S, Xiao, R, Verbovetsky, D, Krukovets, I, Stenina-Adognravi, O, Raman, P, Habib, N, Plow, E, Yendamuri, R

2017

Overview

TGF-β is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-β signaling are process-and stage-dependent, and it is not uncommon that TGF-β exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-β are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-β1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-β1 and mediates the effects of TGF-β1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of TSP-4, and is mediated by activation of SMAD3. Using Thbs4 −/− mice and TSP-4 shRNA, we found that TSP-4 mediated pro-angiogenic functions in cultured EC and angiogenesis in vivo in response to TGF-β1. We observed~3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-β1, and these effects did not occur in Thbs4 −/− animals. Injections of an inhibitor of TGF-β1 signaling SB-431542 also decreased the weights of tumors and cancer angiogenesis. Our results from in vivo angiogenesis models and cultured EC document that TSP-4 mediates upregulation of angiogenesis by TGF-β1. Upregulation of pro-angiogenic TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor growth by TGF-β despite the inhibition of cancer cell proliferation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/51 / 13/95 / 631/67/327 / 631/80/79/750 / 631/80/84/750 / 631/80/86 / 64/60 / Angiogenesis / Angiogenesis Inducing Agents - metabolism / Animals / Apoptosis / Cell Biology / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Cells, Cultured / Chick Embryo / Cytokines / Endothelial cells / Endothelium, Vascular - drug effects / Endothelium, Vascular - metabolism / Endothelium, Vascular - pathology / Extracellular matrix / Female / Gene Expression Regulation - drug effects / Human Genetics / Humans / Internal Medicine / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - pathology / Neovascularization, Pathologic - drug therapy / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - pathology / Oncology / original-article / Protein biosynthesis / Signal Transduction - drug effects / Smad3 protein / Thrombospondin / Thrombospondins - physiology / Transforming Growth Factor beta - pharmacology / Transforming growth factor-b / Transforming growth factor-b1 / Tumors