Figure 1: Regulation of vascular cell signaling by thrombospondin-1 and CD47. A, Angiogenic factors such as VEGF stimulate NO synthesis in endothelial cells by endothelial nitric oxide synthase (eNOS). TSP1 binding to CD47 inhibits activation of the VEGF receptor VEGFR2 and inhibits calciumdependent activation of the VEGFR2 target eNOS. Within endothelial cells, NO activates soluble guanylate cyclase (sGC) to increase angiogenesis, and this enzyme is another target of inhibitory signaling through CD47. NO can also diffuse into underlying vascular smooth muscle where it activates sGC to cause relaxation and increase blood flow. TSP1 in the vessel wall can antagonize this signal via CD47 on vascular smooth muscle cells. NO diffusing into the vascular lumen limits platelet activation, and TSP1 signaling via CD47 blocks this signal to promote platelet aggregation. B, NO can also act on inflammatory cells to inhibit their activation. TSP1 signaling through this pathway may regulate inflammation, and additional signals through CD47 regulate recruitment and interferon-γ and ROS production.