Angiogenesis is a tightly controlled process with important roles in various pathological and physiological conditions. Following myocardial infarction, for example, hypoxia-induced vascular growth factor (VEGF) expression stimulates angiogenesis, which contributes to the reperfusion of damaged tissue. Sphingosine-1-phosphate (S1P) levels are also elevated at the site of infarction, but its role in angiogenesis has remained unclear. Here, Graeme Nixon and co-workers (p. ) show that S1P inhibits angiogenesis and they delineate the molecular pathway underlying this process. To do so, they developed an in vitro angiogenesis model that involves the co-culture of human coronary artery endothelial and smooth muscle cells (ECs and SMCs, respectively) and human fibroblasts. Using this system, they show that S1P inhibits tubule formation, but only when SMCs are present. This effect is mediated by the S1P-induced activation of the RhoA–Rho kinase pathway in SMCs and the subsequent release of tissue inhibitor of metalloproteinase-2 (TIMP-2) from these cells. TIMP-2 release, in turn, prevents the proper formation of endothelial–endothelial cell junctions. Together, these results not only demonstrate a role for SMCs in the regulation of angiogenesis, but also highlight that the angiostatic effects of S1P are highly dependent on the cellular environment.
