Nanoparticle-Mediated Local Delivery Of An Antisense Tgf-Beta 1 Construct Inhibits Intimal Hyperplasia In Autogenous Vein Grafts In Rats

Background: Intimal hyperplasia is one of the most important causes of vascular graft failure. Numerous studies have correlated transforming growth factor-beta 1 (TGF-beta 1) with extracellular matrix (ECM) deposition, a hallmark of intimal thickening.Principal Findings: In the present study, we performed immunohistochemistry, RT-PCR, and Western blot to examine the dynamic expression of TGF-beta 1, TGF-beta 1 receptor type I (TGF-beta RI), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) during intimal hyperplasia in grafted veins of a rat model generated by grafting a portion of the right internal jugular vein to the ipisiliary caroid artery. Additionally, we determined whether nanoparticle-mediated delivery of a TGF-beta 1 antisense-expressing construct prevented TGF-beta 1 expression and intimal hyperplasia in grafted veins. In grafted veins, the expression of TGF-beta 1 significantly increased on day 3 after transplantation, peaked on day 7, slightly decreased on day 14, and returned to baseline levels on day 28. The positive expression of TGF-beta RI in grafted veins remarkably increased on day 7, peaked on day 14, and decreased thereafter. MMP-1 expression decreased significantly, while TIMP-1 expression increased, significantly on days 14 and 28. Nanoparticle-mediated delivery of a TGF-beta 1 antisense-expressing construct down-regulated TGF-beta 1 expression and inhibited intimal hyperplasia in grafted veins.Conclusions: Our findings provide further evidence that TGF-beta 1 plays an integral role in the development of intimal hyperplasia after vascular injury. Nanoparticle-mediated delivery of a TGF-beta 1 antisense-expressing construct is a feasible strategy to target TGF-beta 1-induced intimal thickening.