Mechanisms of TGF-beta-Induced Differentiation in Human Vascular Smooth Muscle Cells

Background: Transforming growth factor-beta (TGF-beta) plays an important role in vascular homeostasis through effects on vascular smooth muscle cells (SMC). Fine-tuning of TGF-beta signaling occurs at the level of ALK receptors or Smads, and is regulated with cell type specificity. Methods: Our goal was to understand TGF-beta signaling in regulating SMC differentiation marker expression in human SMC. Activation of Smads was characterized, and loss-and gain-of-function reagents used to define ALK pathways. In addition, Smad-independent mechanisms were determined. Results: TGF-beta type I receptors, ALK1 and ALK5, are expressed in human SMC, and TGF-beta 1 phosphorylates Smad1/5/8 and Smad2/3 in a time- and dosage-dependent pattern. ALK5 activity, not bone morphogenetic protein type I receptors, is required for Smad phosphorylation. Endoglin, a TGF-beta type III receptor, is a TGF-beta 1 target in SMC, yet endoglin does not modify TGF-beta 1 responsiveness. ALK5, not ALK1, is required for TGF-beta 1-induction of SMC differentiation markers, and ALK5 signals through an ALK5/Smad3- and MAP kinase-dependent pathway. Conclusion: The definition of the specific signaling downstream of TGF-beta regulating SMC differentiation markers will contribute to a better understanding of vascular disorders involving changes in SMC phenotype. Copyright (C) 2011 S. Karger AG, Basel