Vascular remodeling is a response of blood vessels to both physiological and pathological stimuli, leading to either vessel enlargement (positive remodeling) or reduction in vessel diameter (negative remodeling). Examples of remodeling have been observed in fetal development 1 and after graft placement 2-5 or angioplasty. 6 -8 In humans, vascular remodeling but not intimal lesion formation was shown to account for the majority of the restenosis in response to angioplasty procedures. 9,10 We have recently established and characterized a mouse model of arterial remodeling. 11 In this model, flow in the common carotid artery is interrupted by ligation of the vessel near the carotid bifurcation. Using FVB/NJ mice, this resulted in a dramatic reduction in vessel diameter and formation of an intimal lesion. Neointima formation and the influx of inflammatory cells in this model are reduced in P-selectin-deficient mice, while the reduction in vessel diameter is not affected by the lack of P-selectin. 12 Additional specific factors that mediate the remodeling response are beginning to emerge. Several studies have implicated nitric oxide (NO) as an inhibitor of remodeling events. [13][14][15][16][17] Our own studies demonstrated that alterations in blood flow also lead to changes in gene expression of platelet-derived growth factor Achain and B-chain, factors known to modulate proliferation and migration of smooth muscle cells (SMC). 18 Preliminary experiments in our laboratory indicated that there is wide qualitative and quantitative variation in the vascular remodeling response of different mouse strains. To provide the basis for a genetic analysis, we subjected 11 different strains of inbred mice to carotid artery ligation for analysis of the remodeling response. Large differences were found between strains with regards to negative as well as positive remodeling and intimal lesion formation. The magnitude of neointima formation correlated with increased loss of SMC occurring immediately after ligation of the carotid artery as well as enhanced growth properties of SMC in vitro.
Objective-In this study, we characterized the effects of an osteopontin (OPN)-null mutation in normal arterial function and remodeling in a murine model. Methods and Results-OPN-null mutant mice were compared with wild-type mice before and after carotid artery ligation.Before ligation, OPN-null mice had increased heart rate, lower blood pressure, and increased circulating lymphocytes compared with wild-type mice. OPN-null vessels also demonstrated greater compliance accompanied by a loosely organized collagen network. After carotid artery ligation, significant differences were also found in the remodeling response of OPN-null animals. 16,17 and shear stress. 9,18,19 We previously found that inhibiting osteopontin (OPN) function after endothelial denudation led to a significant decrease in the extent of neointimal formation in rats. 20 In this study, the arterial effects resulting from the removal of OPN (product of the spp1 gene) were examined.OPN is a secreted integrin-binding protein that is present in small amounts in uninjured arteries 21 but is abundantly expressed by smooth muscle cells, endothelial cells, 21,22 and activated inflammatory cells [23][24][25] in injured arteries. Abundant OPN expression has also been observed in human atherosclerotic lesions 26 and thoracic aneurysms. 27 The functional significance of this increased vascular expression was suggested by work demonstrating OPN activity as a chemoattractant/adhesive substrate for endothelial cells 28 and vascular smooth muscle cells, 29 an inhibitor of vascular smooth muscle calcification, 30,31 and a chemoattractant/activator of inflammatory cells. 32,33 In vivo studies confirmed these important functions of OPN during tissue remodeling and repair. Chiba et al 34 observed that hematopoietic cell overexpression of OPN resulted in increased atherosclerotic lesion formation. In OPN-null mice, recent data have indicated that the nonredundant functions of OPN in vivo involve widespread participation in tissue remodeling, inflammation, 24,32 tumor progression, 35 and angiogenesis. 36 Defective tissue remodeling on an OPN-null background has been observed in tissues including the myocardium, 37 bone, 36,38 -40 skin, 41 kidney, 42-44 lymph nodes, 45 joints, 46 and malignant tissues. 35 Two phenotypes that characterize many of these studies are a change in the immune response and altered matrix remodeling. Therefore, the widespread participation of OPN in tissue remodeling is likely due to its unique functions in basic repair processes. In addition, the role of OPN as a physiological inhibitor of vascular calcification was demonstrated in studies showing that spontaneous vascular calcification in the matrix of Gla protein-null mice was significantly increased on an OPN-null background. 47 Recently, constitutive overexpression of OPN in mice was observed to result in increased neointima formation after cuffing of the femoral artery. 48 Interestingly, this overexpression of OPN in uninjured mice did not result in accumulation of leukocytes in the vessel...
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