Endoluminal Arterial Injury in Plasminogen-Deficient Mice Steven J. Busuttil, M.D.,* ,1 Carla Drumm, B.S.,* Victoria A. Ploplis, Ph.D.,† and Edward F. Plow, Ph.D.‡ *Case Western Reserve University and Cleveland Veterans Administration Medical Center, Cleveland, Ohio 44106; †W.M. Keck Center for Transgene Research, Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556; and ‡Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Presented at the Annual Meeting of the Association for Academic Surgery, Philadelphia, Pennsylvania, November 18 –20, 1999 Background. Vascular remodeling following arterial injury is characterized by an initial inflammatory re- action. Prior experiments using peritoneal inflamma- tory models have shown that the plasminogen system plays a role in the intensity of the inflammatory re- sponse. This study was undertaken to test the hypoth- esis that an absence of plasminogen would lead to a decrease in vascular remodeling. Methods. A left carotid artery injury was created with a flexible guidewire in both wild-type [Plg(/)] and plasminogen deficient [Plg(/)] mice. The right carotid artery was uninjured and used as a control. Three weeks postinjury, the mice were sacrificed and perfusion fixed, and the bilateral carotid arteries were sectioned for histological examination and collection of morphometric data. Results. After arterial injury, electron microscopy of the acutely injured artery revealed that the endothe- lium was denuded, that there were breaks in the in- ternal elastic membrane, and that there was disrup- tion of the medial layer of smooth muscle cells. The intimal and medial areas were significantly increased between the uninjured and injured carotid arteries of both Plg(/)(80% intimal, 41% medial, P < 0.05) and Plg(/)[48% intimal, 24% medial, P < 0.05) mice. However, although there was a significant in- crease in the adventitial area of Plg(/) mice (18%, P < 0.05), there was no difference in Plg(/) mice (6%). Interestingly, even after 3 weeks, four of six injured arteries in Plg(/) mice had persistent thrombus within the medial layer, whereas this was not found in any of the nine Plg(/) mouse arteries. Discussion. Plasminogen deficiency inhibited the in- crease in adventitial area seen after injury in Plg(/) mice, but not the increase in intimal or medial areas. Not surprisingly, plasminogen-deficient mice also demonstrated a severe alteration in intramural thrombus clearance. Thus, specific aspects of the vas- cular remodeling response are dependent on plasmin- ogen. © 2000 Academic Press Key Words: mice; plasminogen; arterial injury; fibri- nolysis; remodeling. INTRODUCTION Over the last several decades there have been many advances in therapeutic interventions for the compli- cations of atherosclerotic vascular disease. These in- clude platelet antagonists, surgical bypass, and, more recently, endoluminal techniques such as angioplasty and stenting. All vascular interventions are injurious to blood vessels, be it the anastomosis with native tissue or a prosthetic graft, the crush of a “noncrush- ing” vascular clamp, or the expansile and denuding injury associated with angioplasty [1, 2]. Unfortu- nately, as many as one-third of all interventions fail, and this is most evident in endoluminal techniques [3]. Improvements in therapeutic interventions continue to be plagued with the inherent problem of restenosis secondary to remodeling and hyperplasia. The term vascular remodeling is used to describe the healing response of blood vessels in response to injury. In some patients, the healing response is exuberant, leading to restenosis in the area of intervention. Restenosis re- sults in a similar or worse clinical condition, ultimately requiring a repeat intervention in about 25–30% of patients. The response that occurs after vessel injury consists of three phases: an inflammatory phase, a proliferation and migration phase, and a secretory phase [4]. Each phase consists of a complex interaction of several bio- 1 To whom correspondence should be addressed at Section of Vas- cular Surgery 112(W), Louis Stokes VAMC, 10701 East Boulevard, Cleveland, OH 44106. Journal of Surgical Research 91, 159 –164 (2000) doi:10.1006/jsre.2000.5922, available online at http://www.idealibrary.com on 159 0022-4804/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.