The Involvement of ALK5-Smad II Signaling Pathway in Vein Graft Remodeling

Project: Research project

Project Details


Transforming growth factor (TGF)-βfamily had been reported to be involved in pathological conditions like cancer, vascular diseases and fibrosis. Members of TGF-βfamily mediate their effects by binding to a complex of two type I and two type II serine/threonine kinase receptors. Among the seven different types of type I receptors , the most important receptors for regulation of endothelial function by TGF-βare activin receptor-like kinases (ALK)1 and ALK5. A group of specific transcription factors termed “small phenotype and mothers against decapentaplegic related proteins” (Smad) are responsible for subsequent intracellular signal transduction after binding of the ligand. The regulated (R)-Smads are divided in two groups according to the specific type I receptors. One of these groups includes Smad 1, 5, and 8 which are activated by ALK1, 2, 3, and 6. The other group contains Smad 2 and 3 which are activated by ALK4, 5, and 7. Signaling of TGF-βthrough ALK1 and phosphorylation of Smad1/5 induces endothelial cell proliferation and migration. On the other hand, ALK1 induces responses opposite to those of ALK5 and also directly antagonizes ALK5/Smad2/3 signaling. TGF-β is an important factor mediating the phenotypic changes of endothelial cells into mesenchymal cell types which is named as an endothelial-mesenchymal transition (EndMT). Manipulation of TGF-β signaling pathway by conditionally knockout Smad3 prevent the propagation of the fibrotic changes related with EndMT. Neointimal hyperplasia of vein grafts had been reported to be associated with TGF-β-mediated fibrosis and the effect sustained for as long as 6 months in a mice model. In line with the preliminary study of the applicants, we also found an increase of TGF-β protein expression in vein graft tissues. In this new project, the applicant hypothesize that EndMT is involved in vein graft remodeling. Inhibition of ALK5 signaling pathway may attenuate EndMT, reduce fibroblast numbers and neointima thickness. The applicant anticipate in exploring a mechanism contributing to neointima formation and an effective pharmaceutical treatment to reverse the pathologic changes of vein grafts which remain elusive in modern medicine.
Effective start/end date14-08-0115-07-31


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