Reduction of myointimal hyperplasia after arterial anastomosis by local injection of transforming growth factor β3

BackgroundThe transforming growth factor (TGF)-β family of cytokines exerts pleiotropic actions on vascular smooth muscle cell phenotype, proliferation, and extracellular matrix synthesis. This in vivo study assessed the use of TGF-β3 in attenuating the development of postanastomotic smooth muscle cell proliferation.MethodsUnder general anesthesia, 10 adult goats underwent transection and reanastomosis of both common carotid arteries. After reanastomosis, one artery was infiltrated with 50 ng of TGF-β3 in 100 μL of pH buffer around the anastomosis, and the other side was infiltrated with buffer only. After surgery, each animal received 150 mg of aspirin daily. The arteries were explanted after 3 months for histologic examination.ResultsVessel wall thickness surrounding the anastomosis was reduced by 30% after TGF-β3 treatment compared with placebo (P = .003), with a 20% (P = .002) reduction in cellular content. Although total collagen content was not significantly different between TGF-β3 and placebo, collagen type VIII content was reduced around the TGF-β3 anastomoses (P = .011). A reduction in the total elastin content (P = .003) and number of elastic fiber lamellae (P = .042) was found surrounding TGF-β3–treated anastomoses, but not placebo-treated anastomosis. A 29% increase in vasa vasorum (P = .044) was present around TGF-β3–treated anastomoses. No differences in inflammatory cell infiltration were seen between sides.ConclusionsDirect subadventitial infiltration of TGF-β3 immediately after creation of an arterial anastomosis attenuates cell proliferation, with a reduction in elastin and collagen type VIII content and vessel wall thickness.

Clinical RelevancePeripheral arterial bypass graft failure, particularly in the context of critical limb ischemia, has a considerable effect in terms of patient morbidity and mortality, human resources, and financial burden. The predominant etiology of arterial bypass graft failure is encroachment of the vessel lumen by myointimal hyperplasia (MIH). This typically becomes clinically significant 12 to 24 months after surgery. A principal factor in the pathogenesis of MIH development is the proliferation and migration of smooth muscle cells (SMCs) from the tunica media toward the luminal surface. These SMCs dedifferentiate away from the quiescent contractile phenotype ordinarily found in mature vessels into a more immature, synthetic phenotype that is characterized by rapid proliferation and extracellular matrix deposition. The transforming growth factor (TGF)-β family of proteins are multifunctional growth factors that exert a profound influence over the proliferation, extracellular matrix synthesis, and contractile function of numerous cell types. This study demonstrates in an animal model that a single dose of subadventitial TGF-β3 to an artery immediately after wounding attenuates cell proliferation and vessel wall thickness, with a reduction in elastin deposition and collagen type VIII, an important component of the neointima and a promoter of SMC migration and invasion. Thus, TGF-β3 would seem to have potential as prophylaxis against MIH-related bypass graft failure.