Vascular adhesion protein 1 (VAP‐1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo

Abstract

Granulocyte extravasation from the blood into tissues is a prerequisite for a proper inflammatory response. It is regulated by a multistep adhesion cascade consisting of successive contacts between leukocyte surface receptors and their endothelial ligands on vessels. Vascular adhesion protein 1 (VAP-1) is an endothelial surface glycoprotein with two functions. It is an enzyme (monoamine oxidase) and an adhesion molecule for lymphocytes. Its function in binding of granulocytes or in leukocyte trafficking into sites of inflammation in vivo has remained unknown. Here we show that treatment of rabbits with anti-VAP-1 monoclonal antibodies abrogates approximately 70% of granulocyte extravasation into a site of an experimental inflammation. Using intravital microscopy, VAP-1 blockade is shown to increase the velocity of the rolling granulocytes and the frequency of their jerky skippings during the rolling. In addition, the number of firmly bound leukocytes decreased by 44% when VAP-1 was rendered nonfunctional. Our results suggest that VAP-1 functions as a molecular brake early in the adhesion cascade and consequently decreases the firm adherence; it may also directly influence the transmigration step. These data elucidate a new interplayer in the granulocyte extravasation process and provide a novel physiological function for a member of the monoamine oxidase family.

VAP-1 and CD73, Endothelial Cell Surface Enzymes in Leukocyte Extravasation

“…50 Both the anti-VAP-1 antibodies and SSAO inhibitors increase leukocyte rolling velocity and decrease the number of firmly adherent and transmigrated leukocytes in inflamed vascular beds in vivo. 44,49,53 The fact that both anti-VAP-1 antibodies and SSAO enzyme inhibitors diminish leukocyte traffic into sites of inflammation in vivo is in line with the proposed dualistic function of VAP-1. 8 Thus, the antibody binding masks surface epitopes of VAP-1 that are needed for leukocyte binding.…”

“…They have been reported to partially inhibit migration of lymphocytes, granulocytes, or macrophages into inflamed peritoneum, liver, and pancreas. 44,[47][48][49][50] Moreover, SSAO inhibitors also alleviate inflammation in multiple models including colitis, skin inflammation, ischemia-reperfusion injury, sepsis, experimental allergic encephalomyelitis, arthritis, and lung inflammation (Table 1). 17,18,51,52 It is intriguing that an SSAO inhibitor has been very effective in ameliorating clinical disease activity in EAE not only in a pretreatment model but also when the treatment is first started at the peak of disease or at remission.…”

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

“…These data suggest that the decreased numbers of myeloid cells in the SSAO inhibitor-treated mice is not secondary to the decreased tumor volumes. On the basis of our earlier observations (12,30), VAP-1 could play a direct role in supporting myeloid cell binding to the tumor vessels. To test this experimentally, we analyzed in an ex vivo frozen section adhesion assay the binding of purified tumor-infiltrating Gr-1 + myeloid cells to the tumor vessels obtained from tumors grown in vehicle-and SZE5302-treated mice.…”

“…The adhesive function of VAP-1 can be inhibited using function-blocking mAbs or enzyme inhibitors. The anti-VAP-1 Abs inhibit leukocyte-endothelial interactions in several in vitro and in vivo models (8)(9)(10)(11)(12)(13)(14). The small-molecule SSAO inhibitors also effectively attenuate inflammation by diminishing leukocyte rolling, firm adhesion, and transmigration through multiple types of endothelial cells (9,13,(15)(16)(17)(18)(19)(20).…”

Vascular Adhesion Protein-1 and Hepatocellular Cancer

“…VAP-1 expression occurs in the hepatic vascular bed 38,39 . This occurrence suggests that some of the elements of the adhesion cascade in the hepatic vascular bed differ from those in post capillary venules.…”