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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1036-1043.
Prepublished online as a Blood First Edition Paper on September 21, 2004; DOI 10.1182/blood-2004-01-0166.
 Previous Article | Next Article 
Submitted January 14, 2004
Accepted September 14, 2004
Angiostatin is a Novel Anti-inflammatory Factor by Inhibiting Leukocyte Recruitment
Triantafyllos Chavakis, Athanasios Athanasopoulos, Joon-Sup Rhee, Valeria Orlova, Thomas Schmidt-Woll, Angelika Bierhaus, Andreas E May, Ilhan P Celik, Peter P Nawroth, and Klaus T Preissner*
Department of Internal Medicine I, Universitat, D-69115 Heidelberg, Heidelberg, Germany
Institute for Biochemistry, Justus-Liebig-Universitat, D-35392 Giessen, Giessen, Germany
Deutsches Herzzentrum, Technische Universitat, D-80636 Munchen, Munich, Germany
Institute of Theoretical Surgery, Philipps-Universitat, D-35043 Marburg, Marburg, Germany
* Corresponding author; email: klaus.t.preissner{at}biochemie.med.uni-giessen.de.
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 NF B, as well as the NFB-related expression of tissue factor, a potent initiator of haemostasis following vascular injury. Finally, angiostatin forms were generated in vivo following skin injury/inflammation and were detectable during the following entire period of wound healing peaking at the terminal phase of the healing process. Taken together, over and above inhibition of neovascularization, angiostatin was identified as an antiadhesive / antiinflammatory substance. These observations could provide the basis for new therapeutic applications of angiostatin to target chronic inflammatory processes in different pathological situations.
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