Effect of matrix metalloproteinase-9 knockout on vein graft remodelling in mice

Long-term success in vein grafting for bypassing arteries blocked by atherosclerosis is limited by migration and proliferation of smooth muscle cells to form a neointima. Matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are implicated in neointimal formation by freeing smooth muscle cells from the cell-matrix contacts that normally restrict migration. We investigated the role of MMP-9 in vein grafts directly, using knockout mice. Vein grafts in MMP-9(-/-) and wild-type mice had similar luminal and graft areas at 1, 4 and 8 weeks after engraftment, increasing with time. There was a relationship between the perimeter of the external elastic lamina and graft thickness (indicating graft remodelling) in MMP-9(-/-) mice at 1 week after surgery not apparent in control mice until later (r(2) = 0.933 for MMP-9(-/-) mice, r(2) = 0.040 for wild-type mice). Grafts in MMP-9(-/-) mice had 6-fold more pro- and active MMP-2 (p = 0.013, p = 0.026) than grafts in wild-type mice. Grafts from MMP-9(-/-) mice also had more collagen (p = 0.046 at 8 weeks), without any difference in cell number. Thus, while a lack of MMP-9 did not alter vein graft wall area or cellularity, grafts from MMP-9(-/-)mice accumulated more collagen and had earlier linear expansive remodelling, possibly due to an early compensatory increase in MMP-2.