TGF-β induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways

Takahiko Nakagawa, Jin H. Li, Gabriela Garcia, Wei Mu, Ester Piek, Erwin P. Böttinger, Yan Chen, Hong J. Zhu, Duk Hee Kang, George F. Schreiner, Hui Y. Lan, Richard J. Johnson

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138 Scopus citations


Background. Angiogenesis has a key role in numerous disease processes. One of the most important angiogenic factors is vascular endothelial growth factor (VEGF-A), whereas thrombospondin-1 (TSP-1) is a major antiangiogenic factor. Recent studies have shown that VEGF-A as well as TSP-1 is regulated by transforming growth factor-β1 (TGF-β1), but the mechanism remains unclear. Methods. We examined the role of TGF-β1 and its signaling pathways in mediating expression of these two molecules. Rat proximal tubular cells (NRK52E) were stimulated with TGF-β1 to induce VEGF-A and TSP-1 synthesis. To clarify roles of receptor-activated Smads (R-Smads), we blocked Smad signaling using overexpression of the inhibitory Smad, Smad7, and by using fibroblasts from wild-type or knockout mice. To confirm the antiantigenic role of Smads, soluble Fit-1 regulation in response to TGF-β1 was also examined. In addition, the effect of conditioned media from NRK52E and Smad knockout cells was examined on endothelial cell proliferation. Results. Induction of VEGF-A and TSP-1 by TGF-β1 in NRK52E cells was associated with activation of pathway-restricted R-Smads (Smad2 and 3) and blocking these Smads by overexpression of Smad7 blocked their induction. By using of Smad knockout cells, Smad3 was shown to have a key role in the stimulation of VEGF-A expression whereas Smad2 was critical for TSP-1 expression. Consistent with the hypothesis that Smad2 has an antiangiogenic function, we also demonstrated that Smad2, but not Smad3, mediated the expression of VEGF-A antagonist, soluble VEGF-A receptor sFlt-1, in response to TGF-β1. Conditioned media from NRK52E, which was stimulated by TGF-β1 for 24 hours, did not induce endothelial cell proliferation. However, conditioned media from Smad2 knock-out induced endothelial cell proliferation, whereas endothelial cell proliferation was inhibited by Smad3 knockout-derived conditioned media. Conclusion. R-Smads have distinct roles in mediating the expression of pro- and antiangiogenic growth factors in response to TGF-β1.

Original languageEnglish
Pages (from-to)605-613
Number of pages9
JournalKidney International
Issue number2
StatePublished - Aug 2004

Bibliographical note

Funding Information:
Support for these studies was provided by National Kidney Fellowship grant (to Takahiko Nakagawa) by NIH DK-52121 (R.J.), and by a George O'Brien Center grant (P50D4-064233–01) (H.Y.L. and R.J.).


  • Endothelial cell proliferation
  • Smad KO cell
  • TSP-1
  • VEGF
  • sFlt-1


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