found that the interaction of Sema4D with PlexinB1 promoted vasculogenic mimicry while inhibition of Sema4D decreased vasculature (70). cell adhesion (63). Other studies have also elucidated Sema3E/Plexin-D1’s activity to work as a regulatory mechanism for VEGF-induced angiogenesis by modulating the ratio of endothelial tip and stalk cells (24). Studies with Sema 3E?/? mice revealed the important role that avascular zones generated by Sema3E play in guiding cardiac vessel development (48). Further, in a rat model of ischemic stroke, it was shown that Sema3E/Plexin-D1 signaling inhibited angiogenesis through regulation of endothelial dynamic delta-like 4 molecule (64). Within class 3 semaphorins, Sema3C is one of the exceptions due to its bifunctional activity as both a pro-angiogenic and anti-angiogenic factor NG52 (13, 43, 45, 65). studies showed Sema3C to induce endothelial cell proliferation, adhesion and directional migration (43). However, other studies report Sema3C to be significantly anti-angiogenic (13, 45). Pathologic angiogenesis was shown to be inhibited by Sema3C in an oxygen-induced retinopathy model (45). Further, these authors showed that Sema3C inhibits endothelial tube formation when Human Umbelical Vein Cells were cultured with Sema3C conditioned medium. The anti-angiogenic activity of Sema3C was shown by overexpressing Sema3C in U87 glioblastoma cells and assessing formation of neovasculature in chick Rabbit polyclonal to AGPS chorioallantoic membranes (CAM). Sema3C overexpressing U87 cells did not induce new vessels while control U87 cells had extensive vessels on CAMs (66). Therefore, the effects of this semaphorin may be environment dependent and are ultimately controversial. Sema3F contrary to majority of class 3 semaphorins, was shown to promote extraembryonic angiogenesis via inhibition of Myc-regulated throbospondin 1 in yolk sac epithelial cells (50). In contrast, other studies showed that Sema3F is expressed in the avascular outer region of retina and NG52 that it exerts anti-angiogenic effects on the retinal and choroidal capillaries (51). Within class 4 semaphorins, Sema4D was found to have pro-angiogenic effects. Both soluble and membrane-bound forms of Sema4D have been described as pro-angiogenic by signaling through endothelial receptors, Plexin-B1 and Plexin-B2. Interaction of Sema4D with Plexin-B1 stabilizes vasculature. Sema4D has been shown to have potent angiogenic effects both and by inducing endothelial cell chemotaxis, tube formation, cytoskeletal rearrangements, and vessel growth (55, 56). Increased levels of Sema4D have been correlated with poor prognosis in studies of leukemia and mammary carcinoma (67C69). Interestingly, this semaphorin has been shown to play a role in vasculogenic mimicry in a non-small cell lung cancer model. Xia et al. found that the interaction of Sema4D with PlexinB1 promoted vasculogenic mimicry while inhibition of Sema4D decreased vasculature (70). In contrast to Sema4D, Sema4A was found to have dual activity as both a pro- and anti-angiogenic factor. The pro-angiogenic effect of Sema4A in the context of tumor is indirectly mediated by signaling NG52 through Plexin-D1-expressing macrophages, which induce VEGF-A expression and thereby enhance tumor vasculature (52). However, depending on the environment, Sema4A inhibits angiogenesis using the same receptor, Plexin-D1 (53). Therefore, the role of Sema4A in tumors is still controversial. The only member in class 5 semaphorins reported to have angiogenic activity is Sema5A. This semaphorin has been shown to be necessary for normal cranial vasculature development and be a regulator of angiogenesis by promoting endothelial cell migration and proliferation, while also reducing apoptosis (57, 58). Among class 6 semaphorins, Sema6D acts by binding to a receptor complex composed of PlexinA1 and either Off Track (OTK) or VEGFR2. Binding of Sema6D to these receptor complexes results in varying effects during cardiac development including, endothelial cell repulsion or attraction, respectively (2). In models of gastric cancer, signaling due to Sema6D and Plexin-A1/VEGFR2 interaction results in effects similar to VEGF binding alone. In addition, Sema6D/Plexin-A1 expression is positively correlated with the expression of VEGFR2, therefore contributing to its angiogenic and tumorigenic properties (59). Poor prognosis of gastric cancer has been correlated with Sema6D expression and increased angiogenesis (59) (Table 1). Class 7 semaphorins have also been found to have pro-angiogenic effects (Table 1). In particular, Sema7A was determined to mediate angiogenesis through signaling via Plexin-C1 and 1 integrins. Using.
