Figure 1. Cross talk between thrombospondin-1 and nitric oxide (NO) controls angiogenesis. A) Angiogenic signaling induced by vascular endothelial growth factor (VEGF) through its receptor activates Akt, which in turn phosphorylates and activates endothelial nitric oxide synthase (eNOS). The resulting NO binds to and activates soluble guanylyl cyclase (sGC), leading to accumulation of intracellular cyclic-GMP (cGMP). cGMP binds to and activates kinases (cGKs) and cGMP-gated channels (cNG) to stimulate endothelial cell responses required for angiogenesis. Thrombospondin-1 inhibits sGC activation and thereby prevents angiogenic signaling. B) Complementing the blocking of NO signaling by thrombospondin-1, low pro-angiogenic doses of NO suppress thrombospondin-1 expression to remove this inhibitor and facilitate angiogenesis. At higher levels of NO, this feedback is reversed by induction of additional signals that restore expression of inhibitory thrombospondin-1 as well as direct inhibition of angiogenesis by NO-derived reactive nitrogen species.