Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice.

OBJECTIVE: Type 2 diabetes mellitus results in a procoagulant and thrombogenic state that could predispose diabetic individuals to develop venous thrombosis. We sought to determine whether diet-induced type 2 diabetes mellitus affects deep venous thrombosis (DVT) resolution in a murine model. METHODS: C57Bl/6 mice were fed a low-fat or a high-fat diet (n = 10) for 10 weeks, after which DVT was created in the inferior vena cava (IVC) by a combination of low flow and endothelial damage. The IVC and thrombus were harvested at 1 and 2 weeks. Thrombus resolution and neovascularization were investigated through transfemoral angiography (n = 10), thrombus size (n = 4) and weight (n = 10), and nitric oxide synthase 3 immunoquantification (n = 4). Macrophage content was assessed by CD68 immunoreactivity (n = 4). The fibrinolytic system (urokinase plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]) was analyzed by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Total collagen was stained by Sirius red. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were evaluated by zymography and their expressions by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). RESULTS: Diabetic mice had significantly larger and heavier thrombi at 1 and 2 weeks (P < .05), threefold less neovascularization (P < .05), and 35-fold increase in macrophage content (P < .01), than control mice 2 weeks after surgery. IVC recanalization was documented in 90% of 2-week control mice and in 10% of 2-week diabetic mice (P < .01). Increased vein wall collagen and less uPA and more PAI-1 expressions with a decreased uPA/PAI-1 ratio (31%, P < .01) were documented at 2 weeks in diabetic mice. MMP-2 and MMP-9 activities and expressions were significantly increased in diabetic mice at 1 and 2 weeks (P < .05) compared with control mice. CONCLUSION: Diet-induced type 2 diabetes may impair DVT resolution through altered inflammatory, fibrinolytic, and MMP responses.

Matrix metalloproteinase-9 may play a role in recanalization and recurrence after therapeutic embolization of aneurysms or arteries.

PURPOSE: Matrix metalloproteinase (MMP)-9 plays various roles in vascular healing and angiogenesis. This study was conducted to determine if MMP-9 is involved in healing or recanalization after therapeutic occlusion of arteries or aneurysms. MATERIALS AND METHODS: Angiographic and pathologic changes were investigated in canine bilateral venous pouch carotid aneurysms embolized with gelatin sponges with or without previous endothelial denudation, a procedure that can prevent recanalization. To assess a potential role of MMP-9, messenger RNA (mRNA) and protein were compared in denuded and nondenuded aneurysms 4, 7, and 14 days after embolization. To assess if MMP-9 is essential to arterial recanalization, transmyocardial angiography and pathologic findings were compared 14 days after carotid occlusion with platinum coils in MMP-9-knockout and wild-type mice. RESULTS: Denudation of the endothelial lining led to improved angiographic results at 3 weeks (P < .001). Neointimal closure of the aneurysm neck was more complete in denuded versus nondenuded aneurysms. Denudation was followed by a decrease in MMP-9 mRNA (86%, P < .05) and protein (30%, P < .05) 7 days after embolization and a decrease in von Willebrand factor compared with nondenuded aneurysms. MMP-9 immunostaining of axial sections from embolized aneurysms confirmed MMP-9-positive endothelialized clefts, which were absent in denuded aneurysms. Transmyocardial angiography and pathologic examination showed recanalization of one of nine coiled carotid arteries of MMP-9-knockout mice, compared with five of seven controls (P = .035). CONCLUSIONS: MMP-9 may play a role in recanalization of arteries after coil occlusion and in recurrences after sponge embolization of aneurysms.

The effects of stenting and endothelial denudation on aneurysm and branch occlusion in experimental aneurysm models.

BACKGROUND: Stents are increasingly used in the endovascular treatment of intracranial aneurysms. We studied the effects of stenting and endothelial denudation on aneurysm and branch vessel occlusion. METHODS: Bilateral lingual bifurcation venous pouch aneurysms were created in eight dogs, surgically scraping the aneurysmal endothelial lining on one side. Both arteries were immediately stented using balloon-expandable stents. In four other dogs, a wide-neck carotid bifurcation aneurysm was created, with the vein pouch denuded or not (n=2 each), followed by immediate stenting. Results were compared using angiography and pathology at 10 days (n=2), 10 (n=8), and 20 weeks (n=2). Branch occlusion between initial and final angiograms was recorded. Pathological evaluation of aneurysms was studied, with attention to neointima formation at the aneurysm ostium and around branch vessel origins. RESULTS: All stented and denuded lingual aneurysms were obliterated compared with two of eight lingual aneurysms that were stented alone (P=.007). None of the carotid bifurcation aneurysms became obliterated (0/4), but denuded aneurysms showed partial thrombosis (2/2). Of 68 total stent-covered branches, 5 (7%) were occluded and 17 (27%) had altered angiographic flow. CONCLUSIONS: Stenting led to suboptimal results in the presence of an intact endothelial layer. Endothelial denudation can promote aneurysm occlusion when combined with stenting.