Imaging at the inter-face of inflammation and angiogenesis by 18F-fluciclatide PET

Mechanisms underlying atherosclerotic plaque rupture are complex and unpredictable by any current imaging test. However, several key pathogenic processes known to increase the likelihood of an acute plaque event can be tracked in vivo using positron emission tomography (PET). In their Heart paper, Jenkins et al 1 examine the utility of 18F-fluciclatide, an αvβ3integrin-binding PET tracer, for imaging atherosclerosis. This intriguing study adds great momentum in the push to identify novel methods for imaging molecular signatures of high-risk plaques, and raises several important broader considerations for the field. αvβ3 has been extensively studied in atherosclerosis. Endothelial αvβ3 is highly expressed during angiogenesis, where its interactions with extracellular matrix proteins and angiogenic cell surface growth factor receptors promote cell proliferation and mobility. The histological finding of neoangiogenesis is a well-characterised feature of high-risk atherosclerotic plaques. Hypoxic stimuli within plaques trigger new microvessel growth, which are fragile and prone to haemorrhage. Intra-plaque haemorrhage, in turn, results in rapid necrotic core expansion, accumulation of free cholesterol from red cell membranes and intense inflammatory cell infiltration, destabilising the plaque. Endothelial αvβ3 also acts as a mechanotransducer, mediating shear-stress induced pro-inflammatory signalling via NF-kB activation, which further contributes to high-risk plaque formation. In macrophages, αvβ3 helps regulate pro-inflammatory cytokine release, foam cell formation and efferocytosis. αvβ3 is also expressed by migrating smooth muscle cells, differentiating fibroblasts and platelets. In oncology, while there is some evidence to support αvβ3-targeted therapies for disrupting tumour-induced angiogenesis and tumour growth, low concentrations of αvβ3 inhibitors have been shown to paradoxically stimulate angiogenesis by altering αvβ3 and VEGF-R2 trafficking. Its prominent role in the vasculature suggests that blockade of α …