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

Granulocyte extravasation from the blood into tissues is a prerequisite for a proper inflammatory response. It is regulated by a multistep adhesion ca scade 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 enz yme (monoamine oxidase) and an adhesion molecule for lymphocytes, Its funct ion in binding of granulocytes or in leukocyte trafficking into sites of in flammation ill vivo has remained unknown. Here we show that treatment of ra bbits with anti-VAP-1 monoclonal antibodies abrogates similar to 70% of gra nulocyte extravasation into a site of an experimental inflammation, Using i ntravital microscopy, VAP-1 blockade is shown to increase the velocity of t he rolling granulocytes and the frequency of their jerky skippings during t he 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 consequent ly decreases the firm adherence; it may also directly influence the transmi gration step. These data elucidate a new interplayer in the granulocyte ext ravasation process and provide a novel physiological function for a member of the monoamine oxidase family.