Receptor-independent plasminogen activation by urokinase-type plasminogen activator promotes, and adenoviral pai-1 gene transfer inhibits arterial neointima formation in mice

The plasminogen system has been implicated in the proliferation and migration of smooth muscle cells during neointima formation in response to vascular injury. The role of the plasminogen system in these processes is, however, not conclusively demonstrated in vivo. Arterial neointima formation was induced by electric injury in two groups of mice: group I contained mice with deficiency of t-PA (t-PA^-/- ), u-PA (uPA^-/-), combined t-PA:u-PA (t-PA^-/-:u-PA^-/-) and PAI-1 (PAI-1 ') whereas group II contained mice with deficiency of plasminogen (Plg^-/-) and uPAR (u-PAR^-/-), each with their respective control wild type (WT) mice. Percent luminal stenosis (due to neointima formation), within three weeks after electric injury were in group I: 42±l 1% in wild type (WT) mice, 15±5% in u-PA deficient (u-PA^-/-) mice (p=0.045 vs WT), 10±3% in combined t-PA:u-PA deficient (t-PA^-/-:u-PA^-/-) mice (p=0.003), 40±14% in t-PA deficient (t-PA^-/-) mice (p=NS) and 58±10% in PAI-1 deficient (PAI-1^-/-) mice (p=NS) and in group II 10+1% in Plg deficient (Plg^-/-) mice (p=0.001), 27±3% in u-PAR deficient (u-PAR^-/-) mice (p=NS) and 29±5% in WT mice. Neointima formation is thus markedly reduced in mice lacking u-PA-mediated plasmin proteolysis. Proliferation of smooth muscle cells and vascular remodeling were not different in the various genotypes, whereas smooth muscle cell migration was impaired in u-PA^-/- and Plg^-/- mice. Neointima formation in u-PAR^-/- mice was similar to that in WT mice, indicating that binding of u-PA to u-PAR is not required. In addition, intravenous injection of 2times;10⁹ plaque forming units (pfu) of a replication-defective PAI-1 expressin adenovirus (AdCMVPAI-1) but not of control adenovirus (AdRRS) inhibited luminal stenosis in PAI-1^-/- mice (6±5% vs 35±3% luminal stenosis; p<0.05 vs RR5), e.g. to the same extent as in u-PA^-/- mice, suggesting a possible novel therapy for restenosis.