Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis
Shi, C × Patel, A Zhang, D Wang, H Carmeliet, Peter Reed, G L Lee, M E Haber, E Sibinga, N E #
Circulation Research vol:84 issue:8 pages:883-90
Recent studies of mice that lack plasminogen have identified a critical role for this zymogen in arterial remodeling. To permit the use of these (and other) genetically modified mice in the analysis of venous injury, we developed a model in which a patch cut from the external jugular vein of a mouse is grafted to repair a surgically created defect in its carotid artery. In wild-type mice, the venous graft showed initial endothelial denudation and formation of a neointima that progressively and reproducibly expanded in a manner analogous to human vein graft disease, albeit at an accelerated pace. This neointima occupied 37+/-4.6% of the vessel lumen at day 7 and 66+/-5.7% at day 20. The proliferative index of neointimal cells assessed by proliferating cell nuclear antigen staining was 50.6+/-3. 6% at day 7 and 15.2+/-2.0% at day 20. CD45-positive leukocytes and alpha-actin-positive smooth muscle cells accounted for 9.5+/-1.0% and 9.9+/-1.1% of intimal area at day 7, respectively, with the latter increasing to 40.9+/-2.6% at day 20. Collagen accounted for 6.8+/-0.7% of intimal area at day 7 and 20.7+/-1.8% at day 20. Surprisingly, even though arterial neointima formation due to electrostatic and immune-mediated injury is impaired in plasminogen -/- mice, in our study vein graft neointima formation in these mice was not significantly different from that in controls (70.9+/-6.4 versus 65.6+/-4.4% luminal occlusion, P=NS). Thus, plasmin proteolysis, although critical in extracellular matrix degradation and cellular migration after arterial injury, does not appear to be so important in vein graft neointima formation, perhaps because of the relative lack of structural barriers to cellular migration in the normal vein wall. This novel model of vein graft injury should be useful for further studies of differences in the response to injury of arterial and venous tissues.