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.
Thomas
Anita C
AC
Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK. a.thomas@bristol.ac.uk
Newby
Andrew C
AC
D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005260:Female; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013927:Thrombosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology / Q000637:transplantation*; D015854:Up-Regulation; D014654:Vascular Patency; D014684:Venae Cavae / Q000201:enzymology / Q000473:pathology / Q000637:transplantation*
D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse