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(Circulation Research. 2003;92:510.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Urokinase-Type Plasminogen Activator Plays a Critical Role in Angiotensin II–Induced Abdominal Aortic Aneurysm

Gary G. Deng, Baby Martin-McNulty, Drew A. Sukovich, Ana Freay, Meredith Halks-Miller, Therese Thinnes, David J. Loskutoff, Peter Carmeliet, William P. Dole, Yi-Xin Wang

From the Department of Pharmacology and Cardiovascular Research (G.G.D., B.M.-M., D.A.S., A.F., M.H.-M., W.P.D., Y.-X.W.), Berlex Biosciences, Richmond, Calif; The Scripps Research Institute (T.T., D.J.L.), La Jolla, Calif; and The Centre for Transgene Technology and Gene Therapy (P.C.), Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium.

Correspondence to Yi-Xin (Jim) Wang, Berlex Biosciences, Department of Pharmacology, PO Box 4099, 2600 Hilltop Dr, Richmond, CA 94804-0099. E-mail jim_wang{at}berlex.com

We have previously demonstrated that urokinase-type plasminogen activator (uPA) is highly expressed in the aneurysmal segment of the abdominal aorta (AAA) in apolipoprotein E–deficient (apoE^-/-) mice treated with angiotensin II (Ang II). In the present study, we tested the hypothesis that uPA is essential for AAA formation in this model. An osmotic minipump containing Ang II (1.44 mg/kg per day) was implanted subcutaneously into 7- to 11-month-old male mice for 1 month. Ang II induced AAA in 9 (90%) of 10 hyperlipidemic mice deficient in apoE (apoE^-/-/uPA^+/+ mice) but in only 2 (22%) of 9 mice deficient in both apoE and uPA (apoE^-/-/uPA^-/- mice) (P<0.05). Although the expansion of the suprarenal aorta was significantly less in apoE^-/-/uPA^-/- mice than in apoE^-/-/uPA^+/+ mice, the aortic diameters of the aorta immediately above or below the suprarenal aorta were similar between the 2 groups. Ang II induced AAA in 7 (39%) of 18 strain-matched wild-type C57 black/6J control mice. The incidence was significantly higher in atherosclerotic apoE-deficient (apoE^-/-) mice, in which 8 (100%) of 8 mice developed AAA. Only 1 (4%) of 27 uPA^-/- mice developed AAA after Ang II treatment. We conclude the following: (1) uPA plays an essential role in Ang II–induced AAA in mice with or without preexisting hyperlipidemia and atherosclerosis; (2) uPA deficiency does not affect the diameter of the nonaneurysmal portion of the aorta; and (3) atherosclerosis and/or hyperlipidemia promotes but is not essential for Ang II–induced AAA formation in this model.

Key Words: urokinase-type plasminogen activator deficiency • aneurysm • atherosclerosis • vascular inflammation

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