Recent studies identified basic biological principles that are shared by the immune and the nervous system. One of these analogies applies to the orchestration of cellular migration where guidance proteins that serve as a stop signal for axonal migration can also serve as a stop signal for the migration of immune-competent cells. The control of leukocyte migration is of key interest during conditions associated with inflammatory tissue changes such as tissue hypoxia or hypoxic inflammation. Semaphorins are members of these axon guidance molecules. Previously unknown, we report here the expression and induction of semaphorin 7A (SEMA7A) on endothelium through hypoxia-inducible factor 1α during hypoxia. This induction of SEMA7A translates into increased transmigration of polymorphonuclear neutrophil granulocytes across endothelial cells. Extension of these findings demonstrated an attenuated extravasation of polymorphonuclear neutrophil granulocytes in Sema7a-deficient mice from the vasculature during hypoxia. Studies using chimeric animals identified the expression of Sema7A on nonhematopoietic tissue to be the underlying cause of the observed results. Taken together, our findings demonstrate that neuronal guidance proteins do not only serve as a stop signal for leukocyte migration but also can propagate the extravasation of leukocytes from the vascular space. Future antiinflammatory strategies might be based on this finding. endothelia | inflammation R ecent years have identified a close link between hypoxia and inflammation (1). Similar to an acute inflammatory response, hypoxia is marked by increased paracellular fluid exchange and the extravasation of immune-competent cells from the vascular space. Likewise, limited oxygen availability might be the product of the characteristic metabolic changes of inflammation leading to inflammation-associated hypoxia. In addition, proinflammatory cytokines that are released upon stimulation of the immune system might also be part of the hypoxia-enhanced expression of the transcription factor NF-κB (2). Neuronal guidance proteins (NGPs) notably mitigate the course of this process (3-5). For example, cues initially reported to guide neuronal growth and migration, such as netrin-1 or the repulsive guidance molecule (RGM)-A, reduce inflammatory tissue changes (4-6).A member of these NGPs are the semaphorins, a large family of secreted and cell-surface proteins recently found to modulate neurite extension. A member of this family, Semaphorin 7A (SEMA7A), holds the ability to induce the production of cytokines in macrophages and monocytes, which play a significant role during the effector phase of the inflammatory immune response (7,8). Furthermore, SEMA7A also stimulates cytoskeletal reorganization in melanocytes and monocytes, which translates into cell morphology changes that can result in spreading and migration of these types of cells (9-11). However, to date, the role and expression of SEMA7A during hypoxia was unknown.On the basis of these observations, we examined the in...