Emerging roles of neural guidance molecules in atherosclerosis: sorting out the complexity.

N eural guidance cues are attracting attention in athero-sclerosis. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Wanschel et al 1 add yet another neu-ral guidance molecule, Semaphorin 3E, to the growing list of neural guidance cues that may contribute to atherosclerosis. Indeed, this team of scientists, led by Kathryn Moore at New York University, has in the last year implicated 3 other neural guidance cues in atherosclerosis, including netrin-1, 2,3 sema-phorin 3A, 3 and ephrin B 3 in the regulation of inflammatory atherosclerosis. In the first of a series of papers on these molecules, this group showed that netrin-1–deficient bone marrow transplanted into LDLR –/− mice led to markedly reduced athero-sclerotic plaques. 2 Using a method to track monocyte entry and persistence in a quantitative manner, 4,5 the authors argued that netrin-1 was essential for retaining monocyte-derived foamy macrophages in plaques. In the absence of netrin-1, monocytes could enter lesions efficiently but did not stay. 2 Although the key experiment was based on limited observation, a single trial with 3 to 4 mice per group, further evidence for the model includes data that netrin-1 inhibited chemotaxis of a macrophage cell line to CCL19. CCL19 is a ligand for the chemokine receptor CCR7 that seems to be required for regression of atherosclerosis in some models, 6,7 but not others. 5 In the present work, the authors extend the concept laid out in their earlier work on netrin-1 by showing that semaphorin 3E seems to act similarly. Semaphorin 3E was highly expressed in atherosclerotic plaques that progress, whereas it was starkly downregulated in those that regress. 1 Now, using primary cells from the peritoneal lavage, the authors show that chemotaxis to CCL19 is markedly attenuated by exposure to semaphorin 3E. Thus, while the present study did not perform experiments that defined the role of semaphorin 3E in plaque progression or regression , the data lead the authors to suggest that semaphorin 3E fulfills a similar role in promoting macrophage retention in plaques as netrin-1. Future studies will be needed to demonstrate this and to address, for example, why sema-phorin 3E is insufficient to promote retention in the absence of netrin-1, 2 given that the present study suggests they have redundant roles. Perhaps this lack of compensation for netrin-1 in retaining macrophages within plaque is a clue that the role of semaphorin 3E in atherosclerotic plaque is not similar to that …