LRG1 and dysfunctional vessel growth

Neovascularisation plays a key role in the pathogenesis of diseases such as cancer and diabetic retinopathy. Neovessels are frequently disorganised, poorly perfused and leaky resulting in hypoxia, oedema and ineffective delivery of therapeutics. Until recently, most therapeutic strategies have focused on the inhibition or ablation of these vessels but recent evidence suggests that re-directing abnormal vessel growth towards normality is clinically beneficial. Vascular normalisation has gained traction as a therapeutic concept, but its application to human disease is severely hampered by our limited understanding of the factors that subvert normal angiogenesis. A fundamental conundrum is that many of the molecular drivers of normal vascular development are also responsible for pathogenic angiogenesis, indicating that in disease there are additional factors corrupting this process. We recently discovered a secreted pro-angiogenic factor, leucine-rich alpha-2-glycoprotein-1 (LRG1), that is up-regulated in pathogenic settings and disrupts vessel growth, and we have shown that inhibition of LRG1 results in vessel normalisation. In this study, we will investigate the mechanisms that drive pathological angiogenesis, and test the hypothesis that LRG1 subverts endothelial-mural cell interactions by interfering with or redirecting key signalling pathways. The work will increase our understanding of pathological angiogenesis and pave the way towards new therapies.