Plasminogen activator expression correlates with genetic differences in vascular remodeling.

Intima-media thickening (IMT) of the carotid artery, a form of vascular remodeling, correlates well with coronary artery disease risk in humans. Vascular remodeling in response to blood flow is a complex process that critically involves altered cell matrix interactions. To gain insight into these events, we performed partial carotid ligation (left carotid (LCA) = low flow and right carotid (RCA) = high flow) in 2 inbred mouse strains: C57Bl/6J (C57) and FVB/NJ (FVB). To evaluate the role of the 2 major matrix-degrading systems, plasminogen activators (PAs) and matrix metalloproteinases (MMPs), we compared the expression of u-PA, t-PA, MMP-2 and MMP-9 in ligated carotids of C57 and FVB mice. The extent of remodeling was greater in response to low LCA than high RCA flow. Despite a similar decrease in LCA flow in both strains, maximal IMT volume was greater in FVB (82 +/- 7 x 10(-6) microm(3)) than in C57 (38 +/- 4 x 10(-6) microm(3)) after ligation. Among PAs and MMPs, increased expression of t-PA and u-PA correlated with increased IMT (p < 0.0005 and p < 0.001, respectively). MMP-2, MMP-9 and tissue inhibitors of metalloproteinase-2 expression also increased, but did not differ between strains. In summary, flow-induced IMT of the carotid is genetically determined and correlates with t-PA and u-PA expression in 2 inbred mouse strains.

Contrasting effects of urokinase and tissue-type plasminogen activators on neointima formation and vessel remodelling after arterial injury.

Urokinase-type plasminogen activator (uPA) has been implicated in neointima formation and arterial lumen narrowing after angioplasty. To determine the specificity of the action of uPA on vessel remodelling after arterial injury we compared the effects of the recombinant urokinase- and tissue-type plasminogen activators on vessel morphology, cell migration and proliferation. We used a standard model of the balloon catheter injury of the rat carotid artery followed by the periadventitial application to the injured vessel of the one of the recombinant PAs or recombinant alpha(2)-antiplasmin (alpha-AP) in pluronic gel with further immunohistochemistry and morphometry. The perivascular application of alpha-AP immediately after injury attenuated the healing response, significantly reducing neointima size and neointimal SMC numbers. The periadventitial application to the injured artery of recombinant uPA stimulated neointima formation as well as cell proliferation and migration in vivo and induced greater reductions in lumen size than injury alone. In contrast, recombinant tissue-type plasminogen activator reduced the number of neointimal smooth muscle cells and the neointimal area and increased both the lumen area and the area encompassed by the external elastic laminae after balloon catheter injury of the rat carotid artery. In the meantime both PAs nearly doubled medial and adventitial SMC numbers in the vessels. We conclude that the ability to stimulate neointima formation and inward arterial remodelling is a specific property for urokinase plasminogen activator that could not be mimicked by tissue-type plasminogen activator.