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Angiogenesis and inflammation are closely related biologic processes in wound healing and the responses to vascular injury as well as in cardiovascular diseases, however, the molecular connections are poorly defined. In particular, it is yet unclear whether endogenous factors can regulate both angiogenesis and inflammation. Here, we show that the endogenous angiogenesis inhibitor, angiostatin (containing kringle domains 1-4 of plasminogen), serves an anti-inflammatory role, since the kringles 1-3 and its kringle 4 directly interact with leukocyte 1- and 2-integrins, respectively. In particular, a specific interaction between kringle 4 and M2-integrin (Mac-1) but not LFA-1 was identified. Angiostatin thereby inhibited 1- and 2-integrin-mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration through the endothelium in vitro. Moreover, angiostatin blocked the peritonitis-induced neutrophil emigration in vivo. In addition, through its interaction with Mac-1, angiostatin reduced activation of the pro-inflammatory transcription factor NFB, as well as the NFB-related expression of tissue factor, a potent initiator of haemostasis following vascular injury. Finally, angiostatin forms were generated i