Laboratory investigation
Matrix Metalloproteinase-9 May Play a Role in Recanalization and Recurrence after Therapeutic Embolization of Aneurysms or Arteries

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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.

Section snippets

Surgical Construction of Aneurysms and Intraoperative Embolization

Protocols were approved by the institutional committee in accordance with guidelines of the Canadian Council on Animal Care. Beagle dogs (n = 41) weighing 10–15 kg were sedated with acepromazine (0.1 mg/kg), glycopyrrolate (0.01 mg/kg), and butorphanol (0.1 mg/kg), anesthetized with thiopental (15 mg/kg), and maintained under anesthesia with 2% isoflurane. Lateral wall aneurysms were constructed on each common carotid artery (11, 12, 15). Two segments of the same external jugular vein were

Angiographic and Pathologic Results at 3 Weeks

There was no significant difference in the extent of aneurysm exclusion immediately after surgery. At the time of euthanasia, contrast agent filling of crescentic residual or recurrent lesions was significantly less frequent in denuded aneurysms (8%) versus endothelialized aneurysms (84%; P < 0.001; Fig 1a,1b

The aneurysm ostium was more completely occluded in denuded aneurysms. Endothelialized aneurysms typically showed thin neointimal coverage of the sponge that was continuous with

Discussion

Mechanisms responsible for healing or recurrences after endovascular treatment remain poorly understood. Stable angiographic results have been associated with the formation of a thick neointima sealing the neck of aneurysms in human autopsy specimens and animal models, and neointima formation has been the object of extensive research in the cardiology literature (19, 20). Conversely, a recanalization phenomenon can be demonstrated in experimental models and its inhibition by endothelial

Acknowledgments

The authors thank Dr. Yves St. Pierre (Institut Armand Frappier, Laval, QC, Canada) for the gift of MMP-9–knockout mice, which were generated by B. Arnold (Heildelberg University, Heidelberg, Germany) and G. Opdenakker (Rega Institute, Leuven, Belgium).

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    This work was supported by grants from the Canadian Institute of Health research (MOP-44062) and Fondation des Maladies du Coeur du Québec to J.R. None of the authors have identified a conflict of interest.

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