Increased mouse aortic wall expression of MCP-1 and RANTES occurs early in development of elastase-induced AAA and before onset of the chronic inflammatory response. Moreover, elastase directly stimulates AoSMC chemokine production in vitro. Elastase-induced medial SMC production of CC chemokines may therefore provide an important link between enzymatic injury, leukocyte recruitment, and aneurysmal degeneration of the aortic wall.

Background-Pharmacological blockade of ␤ 3 -integrins inhibits neointimal lesion formation in nonmouse animal models of arterial injury. In contrast, ␤ 3 -integrin-deficient (␤ 3 Ϫ/Ϫ ) mice are not protected from neointimal lesion formation after arterial injury. We investigated this discrepancy in ␤ 3 Ϫ/Ϫ and wild-type (␤ 3 ϩ/ϩ ) mice using different models of injury. Methods and Results-After disruption of the carotid with a transluminal probe, there was no significant difference in neointimal thickening between ␤ 3 Ϫ/Ϫ and ␤ 3 ϩ/ϩ mice. However, after ligation of the carotid without medial disruption, there was reduced neointimal thickening in ␤ 3 Ϫ/Ϫ mice compared with ␤ 3 ϩ/ϩ mice at intervals up to 3 months. Lesion reduction in ␤ 3 Ϫ/Ϫ mice was associated with fewer intimal smooth muscle cells (SMCs) without a difference in SMC apoptosis or proliferation rate compared with ␤ 3 ϩ/ϩ mice, consistent with reduced SMC migration from the media into the intima of ␤ 3 Ϫ/Ϫ mice. Moreover, combined eccentric medial disruption and ligation of the carotid in ␤ 3 Ϫ/Ϫ mice resulted in neointimal lesion formation only at the site of medial disruption. Transplantation of bone marrow cells harvested from ␤ 3 ϩ/ϩ mice into irradiated ␤ 3 Ϫ/Ϫ mice resulted in reduced neointimal lesion formation after carotid ligation injury, confirming the importance of ␣ v ␤ 3 and not ␣ IIb ␤ 3 in the attenuated response. Conclusions-The ␣ v ␤ 3 -integrin mediates intimal SMC accumulation that contributes to neointimal thickening in the setting of arterial ligation.

Objective-Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)-deficient (apoE Ϫ/Ϫ ) MMP-9 -deficient (MMP-9 Ϫ/Ϫ ) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation. Methods and Results-Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE Ϫ/Ϫ MMP-9 Ϫ/Ϫ mice had a significant reduction in intimal plaque length and volume compared with apoEMMP-9 ϩ/ϩ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow-derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE Ϫ/Ϫ MMP-9 ϩ/ϩ and apoE Ϫ/Ϫ MMP-9mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development. Key Words: atherosclerosis Ⅲ MMP-9 Ⅲ bone marrow Ⅲ mouse Ⅲ compartmentalization S everal matrix metalloproteinases (MMPs), namely MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-11, and MMP-14, are present in human atherosclerotic lesions, leading to the speculation that overexpression of these enzymes is linked to atherogenesis. [1][2][3][4][5][6] However, experimental models of atherosclerosis demonstrated that mice deficient in apolipoprotein E (apoE) and MMP-3 had larger atherosclerotic plaque, whereas apoE-deficient (apoE Ϫ/Ϫ ) mice overexpressing human MMP-1 had a reduction in plaque size. 1,7 Moreover, inactivation of tissue inhibitor of metalloproteinase 1, which can inhibit MMP-1, MMP-3, MMP-9, and MMP-11 activity and is overexpressed in human atherosclerotic lesions, reduced the plaque size in apoE Ϫ/Ϫ mice. 1 Thus, it is likely that some MMPs are involved in atherogenic processes, whereas others function to inhibit plaque formation. Conclusions-MMP-9 is derived from resident arterial cells and isMMP-9 (gelatinase B) is expressed in late atherosclerotic lesions in humans and has been suggested to mediate plaque instability, a leading cause of acute coronary syndrome and stroke. 2,3 Studies in humans have revealed that polymorphisms in the MMP-9 promoter, which enhance expression, correlate with the development and progression of coronary atherosclerosis. 8,9 Studies with apoE Ϫ/Ϫ MMP-9 Ϫ/Ϫ mice have demonstrated that MMP-9 is critical to intimal plaque size. 10,11 To determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation, we also cross-bred apoE Ϫ/Ϫ mice with MMP-9 Ϫ/Ϫ mice. We demonstrate that although MMP-9 expression is derived mostly from bone marrow cells, MMP-9 derived from resident arterial cells dictates the overall plaque composition. Therefore, MMP-9 activity associated with the resident cells (compartmental...

Although mice deficient in various genes are providing greater insight into the mechanisms of restenosis after angioplasty, there have been limitations with murine models not simulating human vascular disease. To develop a more clinically applicable model of primary atherosclerosis and restenosis following angioplasty of the primary lesion, we fed apolipoprotein E-deficient mice a Western diet and occluded the left common carotid artery for 2 days. Three weeks after flow was restored, the temporarily occluded carotids demonstrated atherosclerotic lesions containing foam cells, cholesterol clefts, necrotic cores, and fibrous capsules. The atherosclerotic carotids in other animals underwent angioplasty with a beaded probe, resulting in plaque and medial layer disruption. Three weeks after angioplasty, although there was significant neointimal lesion formation, the luminal narrowing did not change significantly secondary to overall vessel enlargement (positive remodeling). Neointimal lesions were composed of smooth-muscle cells and extracellular matrix observed adjacent to the original atherosclerotic plaques. Similarly, even at 3 months after the angioplasty the lumen was maintained despite greater neointimal lesion formation caused by progressive positive remodeling. This new murine model of primary atherosclerosis and postangioplasty intimal hyperplasia and remodeling mimics the human disease pattern of postangioplasty intimal hyperplasia. Used in transgenic animals, this model will likely facilitate understanding of the mechanisms of restenosis in humans.