Abstract-Matrix remodeling plays an important role in the physiological and pathological remodeling of blood vessels.We specifically investigated the role of matrix metalloproteinase (MMP)-9, an MMP induced during arterial remodeling, by assessing the effects of genetic MMP-9 deficiency on major parameters of arterial remodeling using the mouse carotid artery flow cessation model. Compared with remodeling of matched wild-type (WT) arteries, MMP-9 deficiency decreased intimal hyperplasia, reduced the late lumen loss, eliminated the correlation between intimal hyperplasia and geometric remodeling, and led to significant accumulation of interstitial collagen. Biochemical analysis of MMP-9 knockout (KO) arterial tissue and isolated smooth muscle cells (SMCs) confirmed the lack of MMP-9 expression or compensation by other gelatinases. To investigate potential mechanisms for the in vivo observations, we analyzed in vitro effects of MMP-9 deficiency on the migration, proliferation, and collagen gel contracting capacity of aortic SMCs isolated from MMP-9 KO and WT mice. Although proliferation was comparable, we found that MMP-9 -deficient cells had not only decreased migratory activity, but they also had decreased capacity to contract collagen compared with WT cells. Thus, MMP-9 appears to be involved not only in degradation, but also in reorganization of a collagenous matrix, both facets being essential for the outcome of arterial remodeling. Our results also establish MMP-9 as an attractive therapeutic target for limiting the effects of pathological arterial remodeling in restenosis and atherosclerosis. Key Words: matrix degradation Ⅲ cell migration Ⅲ restenosis Ⅲ atherosclerosis P hysiological and pathological vascular remodeling in response to a variety of stimuli, including hemodynamic changes, inflammation, and injury, leads to reshaping of the vessel wall. Inappropriate remodeling is currently thought to be the main cause of most prevalent vascular pathologies of arteries, including atherosclerosis and restenosis. 1 Degradation of the matrix scaffold enables cell movement and general tissue reorganization, making specialized enzymes called matrix metalloproteinases (MMPs) 2 prime candidates for agents of vascular remodeling. 3 Although many studies have addressed and endorsed a role for MMPs in pathological remodeling, suggesting these as potential therapeutic targets in restenosis and atherosclerosis, due to the current lack of specific MMP inhibitors, such studies could not resolve the identity of the specific relevant MMP(s). We thus decided to explore the effects of MMP-9 genetic deficiency on the remodeling of carotid arteries in the flow cessation murine model, 4 which allows investigation of both formation of intimal hyperplasia and arterial geometrical remodeling, 5 the two main processes implicated in the stenotic remodeling of human arteries. Materials and Methods Animal ModelMMP-9 expression was disrupted by deletion of most of the exon 2 of the MMP-9 gene in the 129/SvEv genetic background (Jackson La...

MMP-9 induction is associated with the formation of intimal hyperplasia and does not require frank mechanical injury. Our data also show that a significant increase in MMP-9 expression preceded the positive geometrical remodeling of arteries, suggesting a potentially beneficial role for this matrix-degrading enzyme.

Background-Intravascular ultrasound (IVUS) is being used to assess the significance of a left main coronary artery stenosis (LMCS). However, the cutoff values of IVUS parameters at which to predict a fractional flow reserve (FFR) of 0.75 are unknown. Methods and Results-In 55 patients with an angiographically ambiguous LMCS, a pressure guidewire was used to calculate FFR, and IVUS parameters were calculated after automatic pullback. FFR averaged 0.86Ϯ0.13 (range, 0.55 to 1.0). IVUS minimum lumen diameter (MLD), minimum lumen area (MLA), cross-sectional narrowing (CSN), and area stenosis (AS) were 3.8Ϯ0.61 mm, 7.65Ϯ2.9 mm 2 , 59Ϯ13%, and 47Ϯ19%, respectively. Regression analysis demonstrated strong correlations between FFR and MLD (rϭ0.79, PϽ0.0001) as well as between FFR and MLA (rϭ0.74, PϽ0.0001). There were inverse, moderate correlations between FFR and CSN (rϭ0.69, PϽ0.0001), followed by those between FFR and AS (rϭ0.54, PϽ0.0001). Compared with FFR as the "gold standard," an MLD of 2.8 mm had the highest sensitivity and specificity (93% and 98%, respectively) for determining the significance of an LMCS, followed by an MLA of 5.9 mm 2 (93% and 95%, respectively). Based on an FFR Ͻ0.75 and an FFR Ն0.75, the 38-month survival and event-free survival estimates (EFSEs) were both 100% and 100% versus 90%, respectively (PϭNS). Conclusions-We conclude that (1) an IVUS MLD and MLA of 2.8 mm and 5.9 mm 2 , respectively, strongly predict the physiological significance of an LMCS and (2) among patients with an LMCS, an FFR of 0.75 is a strong predictor of survival and EFSE.

Background-Recent observations associate plaque instability with expansive arterial remodeling, suggesting a common driving mechanism. Methods and Results-To demonstrate that macrophages, a characteristic of vulnerable plaques, also assist in expansive remodeling, we compared carotid artery remodeling due to formation of experimental macrophage-rich and macrophage-poor lesions in the flow cessation model in hypercholesterolemic apolipoprotein E knockout (ApoE KO) and wild type (WT) mice. After ligation, macrophages started to rapidly accumulate in ApoE KO but not in WT carotid artery lesions. Macrophage-rich ApoE KO intimal lesions grew fast, typically occluding within 14 days, despite a tripling of the vessel area. Outward remodeling of macrophage-rich ApoE KO arteries positively correlated with macrophage area (r 2 ϭ0.600, PϽ0.001). To investigate potential mechanisms of macrophage-enabled expansive remodeling, we compared levels of matrix metalloproteinases in homogenates of macrophage-rich and macrophage-poor carotid arteries. Gelatinolytic activity of macrophage-rich lesions increased faster and reached maximal levels several fold higher than in the macrophage-poor WT lesions. Conclusions-Our results suggest that macrophages facilitate expansive arterial remodeling through increased matrix degradation by matrix metalloproteinases. This initially favorable remodeling action may eventually increase the vulnerability of macrophage-rich atherosclerotic plaques.

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