Macrophage-Derived Matrix Metalloproteinase-2 and -9 Promote the Progression of Cerebral Aneurysms in Rats

Abstract

Background and Purpose-Mechanisms of initiation, progression and rupture of cerebral aneurysms have not yet been fully understood despite its clinical significance. Matrix metalloproteinases (MMPs) are a family of proteinases which are involved in the remodeling of vascular walls. In the present study, we investigated the significance of MMPs in the progression of cerebral aneurysms. Methods-Cerebral aneurysms were experimentally induced in 7-week-old male Sprague-Dawley rats. MMP-2 and MMP-9 expression was examined by immunohistochemistry and RT-PCR. Gelatinase activity in aneurysmal walls was assessed by in situ zymography. A selective inhibitor for MMP-2, -9 and -12, tolylsam, was used to examine the effect of inhibition of MMP-2 and MMP-9. Results-Macrophages infiltrated in arterial walls of experimentally induced rat cerebral aneurysms and expressed MMP-2 and -9. Macrophage infiltration and MMP expression was increased with the progression of aneurysms. Gelatinase activity attributable to MMP-2 and MMP-9 increased in arterial walls of rat cerebral aneurysms. Furthermore, tolylsam reduced the ratio of advanced aneurysms in our rat model. Conclusions-These data suggest that macrophage-derived MMP-2 and -9 may play an important role in the progression of cerebral aneurysms. The findings of this study will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease.

TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

“…15 This may, in part, explain how inflammatory cells and cytokines promote vascular wall remodeling and aneurysm formation. 28,30 In summary, results of the present studies provide novel in vitro and in vivo evidence showing that TNF-a profoundly suppresses expression of SMC differentiation genes and myocardin while concomitantly activating expression of KLF4 and matrix remodeling/inflammatory genes. Although phenotypic modulation cannot be directly tested in cerebral aneurysms as carried out in cultured SMCs and rat carotid arteries-a model of intracranial atherosclerosis 20,21 -TNF-a was increased early in an animal model of aneurysm formation in parallel with changes in expression of the SMC marker gene SM-a-actin, SM-MHC, KLF4, and proinflammatory/matrix-remodeling genes in a similar fashion.…”

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

“…Macrophage infiltration and activation play key roles in prolonged inflammation and are associated with the growth of IAs 9. As shown in Figure 2A, Iba1‐positive macrophages had less infiltration into the IAs of the anagliptin‐treated group than those in the vehicle group (Figure 2A).…”

“…Chronic inflammation involves the infiltration of monocytes/macrophages11 and the subsequent release of proinflammatory cytokines, chemokines,11 and matrix‐degrading proteinases, such as matrix metalloproteinases,9 that induce cell death and the destruction of the extracellular matrix, causing the thinning of the aneurysmal wall. Inhibiting NF‐κB and ETS‐1 (E26 transformation–specific sequence 1) with chimeric decoy oligodeoxynucleotides decreases expression of MCP‐1 and macrophage infiltration in rat IA models,12 indicating that inflammatory processes play a crucial role in the formation and growth of IAs.…”

“…Accordingly, the DPP‐4 inhibitor anagliptin prevents the progression of atherosclerosis7 and abdominal aortic aneurysms8 by mitigating macrophage activation and accumulation. During the growth of IAs, macrophage infiltration disrupts the extracellular matrix through the secretion of macrophage‐derived matrix metalloproteinases including MMP‐2 and MMP‐9 9. In this study, we focused on the anti‐inflammatory effects of a DPP‐4 inhibitor and examined whether anagliptin prevents the growth of aneurysms in an experimentally induced IA model.…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…The authors also concluded that the decrease in media thinning results from mast cells' modulation of MPP-2 and MMP-9 expression. [17,19] Overall, these data suggest that the degranulation of mast cells plays a role in IA formation.…”