The role of vascular endothelial growth factor in restenosis: the controversy continues.

In 1996, the late Jeffrey Isner proposed the use of vascular endothelial growth factor (VEGF) gene delivery in patients undergoing percutaneous transluminal angioplasty as a strategy to limit the risk of restenosis.1VEGF promotes endothelial cell function and is a potent stimulator of endothelial cell migration and survival. Because normal endothelium inhibits smooth muscle cell proliferation, it was hypothesized that accelerating the reendothelialization of the balloon-injured site would diminish the severity of restenosis. Indeed, reports in animal models demonstrate that local administration of VEGF-A or VEGF-C leads to accelerated reendothelialization and a reduction in intimal thickening.2–5 However, the utility of VEGF or other proangiogenic factors for the treatment of restenosis is questioned by reports that have documented extensive vascular networks in atherosclerotic plaques6 and balloon-injured coronary arteries.7 Thus, the delivery of proangiogenic agents might exacerbate the growth of vascular lesions, analogous to the concept that angiogenesis contributes to tumor growth. These concerns are supported by studies showing that treatment of apolipoprotein E (ApoE)-deficient mice with an angiogenesis inhibitor reduced intimal neovascularization and plaque growth,8 and administration of VEGF enhanced atherosclerotic plaque progression, which was associated with increased capillary density.9 See pp 2424, 2430, 2436, 2444 This controversy has been rekindled by 3 articles appearing in the present issue of Circulation .10–12 Although many of the previous studies focused on the effects of exogenously administered angiogenic growth factors on vascular lesions, these new studies analyze the role of endogenous angiogenic growth factor signaling in neointima formation after acute vascular injury. Specifically, these studies tested whether VEGF-Traps (Figure), inhibitors of endogenous VEGF signaling, have a positive or negative effect on the process of intimal hyperplasia. On the basis of these new studies, we can conclude that VEGF inhibits restenosis,10 VEGF promotes restenosis,12 …