Journal
JOURNAL OF VASCULAR RESEARCH
Volume 48, Issue 6, Pages 485-494Publisher
KARGER
DOI: 10.1159/000327776
Keywords
Smooth muscle cell; Smad; Transforming growth factor beta; ALK receptor; Signaling
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Funding
- National Institutes of Health from the National Center for Research Resources [R01HL070865, P20RR15555, R01HL65301]
- American Heart Association
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR015555] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL070865, R01HL065301] Funding Source: NIH RePORTER
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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
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