Urokinase Increases the Content and Activity of Matrix Metalloproteinases 2 and 9 during <Emphasis Type="Italic">in Vivo</Emphasis> Constrictive Arterial Remodeling

Russian Research and Production Center of Cardiology, Moscow. Ad dress for correspondence: [email protected]. E. V. Parfenova Remodeling of the vascular wall is a critical stage in the pathogenesis of vascular diseases, including arterial hypertension, atherosclerosis, and restenosis after balloon angioplasty [2,6,11,12]. Urokinase plasminogen activator (urokinase) plays a key role in arterial remodeling after balloon angioplasty [2,7]. Our previous studied showed that urokinase stimulates the formation of neointima and constrictive arterial remodeling after experimental balloon angioplasty. However, tissue plasminogen activator decreases the count of neointimal cells and prevents negative remodeling of the artery after balloon injury [3-5]. Migration and proliferation of vascular cells (smooth muscle cells, SMC; leukocytes; and fibroblasts) and remodeling of the extracellular matrix are the key stages in remodeling of the vascular wall. They are accompanied by the formation of neointima and neoadventitia and narrowing of the artery lumen [6,11,12]. These processes are regulated by growth factors and protease system of plasminogen activators, plasmin, and matrix metalloproteinases (MMP) [2,13,14]. Cell migration requires activation of extracellular proteolysis under the influence of not only plasmin and urokinase, but also of MMP. Plasmin initiates transformation of inactive MMP into active compounds [1,7,8,10,13]. The study of transgenic animals not having the genes for MMP2 and MMP-9 showed that MMP modulate migration of cells in the vascular wall, formation of neointima, and narrowing of the artery lumen after injury [9]. Administration of nonselective synthetic MMP inhibitors (batimastat and marimastat) and transfection with type 1 and 2 tissue inhibitors of MMP (TIMP-1 and TIMP-2) suppress the formation of neointima and prevent narrowing of the lumen in damaged artery [7,9]. It remains unclear whether the differences in the effect of urokinase and tissue plasminogen activator in the vascular wall are in vivo mediated by changes in the activity and expression of MMP. Here we studied the effect of urokinase on expression and activity of MMP after experimental balloon injury of the artery. We assayed the early process of neointima formation and arterial remodeling.