Antisense to Transforming Growth Factor-β1 Facilitates the Apoptosis of Macrophages in Rat Vein Grafts

Abstract

Background: The success of peripheral vein grafts is limited by intimal hyperplasia. Transforming growth factor (TGF)-β₁ has effects on cell proliferation, apoptosis and extracellular matrix synthesis. We have previously observed positive changes in vessel healing with antisense to TGF-β₁. Methods: Adenovirus was used to transduce rat femoral artery vein grafts with antisense to TGF-β₁ (Ad-AST) or the sequence encoding the bioactive form of TGF-β₁ (Ad-BAT). Grafts were harvested at 1, 2, 4 and 12 weeks and formalin fixed for immunohistochemical studies of the cell markers proliferating cellular nuclear antigen (proliferation) and active caspase 3 (apoptosis). In situ DNA fragmentation assays were also performed to confirm active caspase 3 results. Results: Ad-AST treatment significantly (p = 0.05) increased apoptosis of macrophages inside the internal elastic lamina. In addition, Ad-AST treatment significantly increased the cellularity of the graft at early time points and reduced it at later time points (p = 0.01). Conclusion: The low levels of TGF-β₁ in Ad-AST treatment promote apoptosis of macrophages and provide an environment that is more conducive to the proliferation or infiltration of cells that contribute to healthy vessels.