Increased expression of urokinase during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth.
Overexpression of urokinase plasminogen activator (uPA) in endothelial cells can decrease intravascular thrombosis. However, expression of uPA is increased in atherosclerotic human arteries, which suggests that uPA might accelerate atherogenesis. To investigate whether elevated uPA expression accelerates atherogenesis, we cloned a rabbit uPA cDNA and expressed it in carotid arteries of cholesterol-fed rabbits. uPA gene transfer increased artery-wall uPA activity for at least 1 week, with a return to baseline by 2 weeks. One week after gene transfer, uPA-transduced arteries were constricted, with significantly smaller lumens and thicker walls, but no difference in intimal or medial mass. Two weeks after gene transfer, uPA- and control-transduced arteries were morphologically indistinguishable. By 4 weeks, however, uPA-transduced arteries had 70% larger intimas than control-transduced arteries (P < 0.01) and smaller lumens (P < 0.05). Intimal lesions appeared to be of similar composition in uPA- and control-transduced arteries, except that degradation of elastic laminae was evident in uPA-transduced arteries. These data suggest that elevated uPA expression in atherosclerotic arteries contributes to intimal growth and constrictive remodeling leading to lumen loss. Antagonists of uPA activity might, therefore, be useful in limiting intimal growth and preventing constrictive remodeling. Overexpression of uPA in endothelial cells to prevent intravascular thrombosis must be reconsidered, because this intervention could worsen underlying vascular disease.
Falkenberg
Marten
M
Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, University of California, San Francisco, CA 94141-9100, USA.
Tom
Clifford
C
DeYoung
Mary Beth
MB
Wen
Shan
S
Linnemann
Ruth
R
Dichek
David A
DA
D000818:Animals; D030801:Animals, Genetically Modified; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D002339:Carotid Arteries / Q000473:pathology*; D002461:Cell Line, Transformed; D003251:Constriction, Pathologic; D018076:DNA, Complementary; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D011817:Rabbits; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D018076:DNA, Complementary; D014568:Urokinase-Type Plasminogen Activator