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.

Established neointimal hyperplasia in vein grafts expands via TGF-β-mediated progressive fibrosis

“…The inhibition of TGF-␤ attenuated an early neointimal hyperplasia induced in bypass vein grafts as well as injured arteries (4,45). Further mechanistic studies suggest that this is ascribed to its function in regulating fibroblast recruitment, macrophage survival, and neointimal cell proliferation (15,19,23). TGF-␤ is a pleiotropic cytokine with multiple bioactivities functioning in a context-dependent manner (8,28).…”

The effects of indoxyl sulfate-induced endothelial microparticles on neointimal hyperplasia formation in anex vivomodel

“…Animal models of artificial vascular injury have demonstrated that TGF-β administration or overexpression markedly enhanced NH at the site of vascular injury [71011]. Other studies have shown that upregulated TGF-β secretion plays a critical role in neointima formation via fibroblast recruitment, the regulation of inflammatory macrophage survival, and enhancement of matrix deposition [5192021]. Both TGF-β mRNA and protein levels have been shown to be upregulated immediately after vascular injury and sustained over 3 months [5].…”

Smooth muscle cell-specific Tgfbr1 deficiency attenuates neointimal hyperplasia but promotes an undesired vascular phenotype for injured arteries

“…These temporal and cell-type-specific TGFb issues must be addressed prior to advancing existing anti-TGFb treatments to prevent vascular restenosis. In addition, previous preclinical studies of anti-TGFb therapies focused primarily on neointimal thickening, with less attention being paid to other phenotypic traits, such as SMC differentiation and status of local inflammation (Wolf et al 1994;Kingston et al 2001;Ryan et al 2003;Heaton et al 2008). Finally, recent studies (Li et al 2014;Hu et al 2015), including our previous study (Schmit et al 2015), have demonstrated that an acute loss of SMC TGFb breaks aortic wall homeostasis and induces spontaneous aortic aneurysm formation.…”