Lock 'n' roll with VAP-1

Leukocyte extravasation through the endothelium is regulated by adhesion and signaling molecules. Now, vascular adhesion protein-1 (VAP-1) joins the group of signaling molecules involved in this process.

In an interesting study published in this issue of Blood, Jalkanen and colleagues describe the important signaling function of VAP-1 in leukocyte extravasations. VAP-1 is a bifunctional cell-surface glycoprotein, having adhesive and enzymatic properties. As a membrane-bound form, it is found in many tissues and organs, especially in adipocytes, endothelial cells, and smooth muscle cells, and is responsible for leukocyte trafficking at inflammation sites. The enzymatic activity of VAP-1 belongs to the semicarbazide-sensitive amine oxidase (SSAO) family.¹  However, the functional role of SSAO remains unclear and is one of the growing numbers of proteins that have disparate functions.²  It converts primary amines into their corresponding aldehydes, while generating H₂O₂ and NH₃. These highly reactive aldehydes can initiate protein cross-linking, formation of advanced glycation end-products, artherogenesis, and glucose regulation.³  Increased serum SSAO activities are found in patients with diabetes mellitus, vascular disorders, liver cirrhosis, and Alzheimer disease.⁴ 

Jalkanen's laboratory has a long productive history of dissecting VAP-1–mediated leukocyte trafficking to sites of inflammation and the importance of this molecule as a potential target for anti-inflammatory therapies. In their present study, using human endothelial cells transfected with wild-type VAP-1 and an enzymatically inactive VAP-1 point mutant, the authors show that transcription and translation of 2 adhesion molecules (E- and P-selectin) are induced through the enzymatic activity of VAP-1. Moreover, the use of VAP-1–deficient animals and VAP-1–deficient animals carrying human VAP-1 as a transgene showed VAP enzyme activity–dependent induction of P-selectin in vivo. These data suggest a novel physiological function for a member of the monoamine oxidase family. So far, cross-talk between adhesion molecules has been shown to play a role during the later phase of the extravasation cascade. The results of Jalkanen and colleagues now extend cross-talk to the very early steps of the cascade.

Very little is known about the regulation and origin of circulating SSAO/VAP-1 and its relation to the membrane-bound form. An important characteristic of the membrane-bound VAP-1 is its ability to cause leukocytes to roll very slowly, presumably allowing for more effective and firm adhesion. VAP-1 blockade is shown to increase the velocity of the rolling granulocytes and the frequency of their jerky skipping during the rolling.⁵  In addition, the number of firmly bound leukocytes decreased by 44% when VAP-1 was rendered nonfunctional. This suggests that the adhesion molecule VAP-1 functions as a molecular lock early in the adhesion cascade and consequently increases firm adherence, whereas the enzymatic form influences the rolling step by altering the expression of selectins. Whether only T cells or granulocytes use VAP-1 to roll, or whether this also extends to other leukocytes following activation, remains to be established. Future work will have to be done to determine what the relevant ligands for VAP-1 might be. While many aspects of VAP-1 multiple function remain to be explored, the present paper makes the important step of linking this molecule to signaling functions.