Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been implicated in atherogenesis and has been shown to have both pro-and antiatherogenic properties. Neointimal thickening is a prominent feature of early atherogenesis. This study aimed to examine the role of GM-CSF in neointimal formation induced by endothelial injury using a GM-CSF À/À mouse model. Neointimal thickening was induced by endothelial damage in the common iliac arteries of normolipidemic C57Bl/6 (wild-type) and GM-CSF À/À mice. Arteries were collected weekly for 3-7 weeks following surgery. A significant delay in neointimal formation in the GM-CSF À/À compared with wild-type mice was detected by morphometric analysis of the intimal area. Neointimal size was B10% smaller in GM-CSF À/À mice at 4-6 weeks post-surgery, compared with wild-type mice. The neointima was composed predominantly of smooth muscle cells and there was no difference in the extent of endothelial cell coverage between the wildtype and GM-CSF À/À mice. Using immunohistochemistry, reduced macrophages (F4/80 + cells), proliferating cells (proliferating cell nuclear antigen (PCNA) + cells) and platelet-derived growth factor-B were detected within the arteries of GM-CSF À/À mice compared with wild types at 4 weeks post-surgery. GM-CSF À/À mice had reduced connective tissue within the neointima compared with wild types at 5 weeks post-surgery, determined by trichrome staining. We conclude that GM-CSF deficiency reduces neointimal formation in a normolipidemic model, primarily due to reduced macrophage recruitment.

Abstract. Interferon (IFN)-γ has been implicated in restenosis, however its precise role in the pathophysiology of neointimal formation following angioplasty is unclear, as it has been shown to both promote and inhibit neointimal formation. Dietary-induced hypercholesterolemia enhances injurymediated neointimal formation, associated with increased systemic inflammation and serum IFN-γ. This study examined the effect of IFN-γ gene deficiency ( -/-) on neointimal formation in a mouse model of endothelial injury combined with an atherogenic diet. Neointimal formation was induced via endoluminal endothelial injury of the common iliac arteries of IFN-γ -/-and wild-type (WT) C57Bl/6 mice. Histopathological analysis of the arteries was performed at 3 and 6 weeks postsurgery. IFN-γ -/-mice demonstrated a significant reduction in neointimal formation at the 3-week time point, compared to their WT counterpart. No significant differences in plasma lipid profile and the extent of re-endothelialization were detected between IFN-γ -/-and WT mice, suggesting that the effect of IFN-γ on neointimal formation is due to injury-mediated vessel neointimal responses. In support of the histopathological findings, immunohistochemical analysis revealed a significant reduction in vessel infiltrating macrophages, and neointimal PDGF-B expression, vascular smooth muscle cell composition and cellular proliferation in the IFN-γ -/-mice, in comparison to their corresponding WT group at the 3-week time point. In conclusion, the IFN-γ-mediated pathway plays an important role in inflammatory responses and proliferative effects following injury, suggesting that modulation of the IFN-γ pathway would be beneficial in controlling neointimal formation and restenosis. IntroductionRestenosis is a common and serious complication associated with re-vascularisation by percutaneous coronary angioplasty, with considerable clinical implications (1). Inflammatory-mediated mechanisms following endothelial injury and/or stent placement are thought to play a pivotal role in restenosis (1). Moreover, injury-induced proliferation and/migration of vascular smooth muscle cells (VSMCs) is an important contributor to neointimal hyperplasia and in-stent restenosis (2,3). However, the precise underlying molecular mechanism(s) of restenosis are not entirely understood.The pro-inflammatory cytokine interferon (IFN)-γ exhibits many biological functions including; mediation of inflammatory responses and immunomodulatory effects (4,5). IFN-γ is secreted from a variety of cells such as T helper cell type 1 (Th1) lymphocytes, activated macrophages, VSMCs and natural killer cells, and its expression has been demonstrated in atherosclerotic lesions (4,6). IFN-γ affects major cell types within the lesion and displays a complex role in vascular lesion development and progression (4). The biological effects of IFN-γ include; stimulating the differentiation of monocytes to macrophages, activation of macrophages and T-lymphocytes (4), and increasing the expression of platelet-derived...

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