Formation of the vascular system during embryonic development, the physiological response to hypoxia or tissue injury in the adult, occurs through sprouting angiogenesis. Angiogenesis occurs primarily through VEGF-A binding to VEGFR2, which controls a diverse range of endothelial cell functions, including proliferation and sprouting, but importantly also controls vessel leakage (permeability). Both vascular permeability and angiogenesis are regulated by cell-cell adhesion within the vessel wall, which is controlled by the junctional localisation of VE-cadherin. We have shown that VE-cadherin localisation is mediated by the VEGFR2/TSAd/c-Src pathway, which is essential for recruitment of c-Src kinase to cell-cell junctions to phosphorylate VE-cadherin. Once phosphorylated, VE-cadherin is internalised and cell-cell adhesion is lost, promoting both sprouting angiogenesis and vessel leakage. While the VEGFR2/TSAd/c-Src/VE-cadherin pathway plays a crucial role in regulating permeability and angiogenesis events, how broadly it is active in different vascular beds and pathological or physiological settings is unclear. Using a range of inducible, conditional knock-out mouse models, we have observed the VEGFR2/TSAd/c-Src/VE-cadherin pathway controls angiogenesis in peripheral organs but it does not act during developmental angiogenesis in the retina. Excitingly, while this pathway is not active in normal retinal angiogenesis, we have found it is important for driving pathological angiogenesis and vascular stability in the retina in a model of oxygen-induced retinopathy. These results reveal this pathway plays distinct roles in developmental and pathological angiogenesis and may be an attractive target to promote vascular normalisation in pathological contexts.