Activation of sterol regulatory element-binding proteins (SREBPs) is critical in IL-8-induced angiogenesis

Angiogenesis is essential in many physiological and pathological processes and can be stimulated by many different factors. To better understand and to manipulate this process more effectively, it would be beneficial to identify molecules common to the signaling pathways stimulated by different classes of angiogenic factors. Sterol regulatory element-binding proteins (SREBPs) are involved in the metabolism of cholesterol and fatty acids, molecules that are critical in membrane biology, and hence, many of the processes involved in angiogenesis. Here, we show that angiogenic factors of different families, such as basic fibroblast growth factor, thrombin, and interleukin (IL)-8, stimulate SREBP activation, whereas nonangiogenic factors, such as transforming growth factor-beta1, do not. We focused our detailed studies on IL-8 in vitro and in vivo, as this chemokine is also involved in inflammation and hence, has the potential to be critical in inflammation-induced angiogenesis, a process common to many diseases. Using human microvascular endothelial cells, a rabbit skin wound-healing model, and the chorioallantoic membrane assay, we show that IL-8 stimulates the activation of SREBP-1 and -2, and this activation is specific and receptor-mediated. SREBP activation leads to activation of RhoA through 3-hydroxy-3-methylglutaryl CoA reductase. RhoA is a small guanosinetriphosphatase, important in cytoskeletal functions, which in turn, are critical in many of the cellular processes needed for angiogenesis. Given that diverse, angiogenic factors use different cell-surface receptors, identification of this common step in the signal-transduction pathway provides the opportunity for novel approaches for prevention and treatment of diseases involving abnormal angiogenesis.