Abstract
Proteoglycans are produced and secreted by vascular smooth muscle cells, but the pathophysiological role of these glycoproteins in the vasculature is an enigma. Because the small leucine-rich proteoglycan (SLRP) biglycan is overexpressed in arteriosclerotic lesions, we produced mice constitutively overexpressing biglycan in the vascular smooth muscle, in order to examine the effects on vascular pathology. In the aorta and renal vasculature, increased vascular proliferation was seen both in the basal state and after infusion of angiotensin II (Ang II) in the transgenic mice compared with wild-type controls. In addition, the combination of biglycan overexpression and Ang II infusion resulted in marked increases in vascular smooth muscle cell proliferation and migration in the coronary arteries, as well as increases in fibrosis surrounding the vessels. In vitro, biglycan caused an increase in thymidine incorporation and migration of vascular smooth muscle cells, whereas these parameters were unchanged or reduced in endothelial cells. Moreover, addition of biglycan resulted in an increase in cdk2 expression and decrease in p27 levels in the vascular smooth muscle cells. These results suggest that this extracellular matrix SLRP may be involved in the regulation of vascular smooth muscle growth and migration through cdk2- and p27-dependent pathways. Furthermore, changes in biglycan expression could be a factor influencing the susceptibility of arteries to vascular injury, and may play a direct role in the pathogenesis of vascular lesions.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Angiotensin II / genetics
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Angiotensin II / pharmacology
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Animals
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Aorta / metabolism
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Aorta / ultrastructure
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Arterial Occlusive Diseases / etiology*
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Arterial Occlusive Diseases / genetics
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Arterial Occlusive Diseases / metabolism
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Arterial Occlusive Diseases / pathology
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Arterioles / metabolism
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Arterioles / ultrastructure
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Biglycan
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CDC2-CDC28 Kinases / genetics
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CDC2-CDC28 Kinases / physiology
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Cattle
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology
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Cell Division
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Cell Movement
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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Coronary Vessels / metabolism
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Coronary Vessels / ultrastructure
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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Disease Susceptibility
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Endothelial Cells / cytology
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Extracellular Matrix Proteins
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Gene Expression Regulation
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Humans
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Kidney / blood supply
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Male
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Mice
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Mice, Transgenic
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Muscle, Smooth, Vascular / cytology*
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Muscle, Smooth, Vascular / injuries
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Myocytes, Smooth Muscle / cytology*
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Myocytes, Smooth Muscle / physiology
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Organ Specificity
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Promoter Regions, Genetic / genetics
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Proteoglycans / biosynthesis
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Proteoglycans / genetics
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Proteoglycans / physiology*
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Rats
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Rats, Wistar
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / physiology
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Renin / blood
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
Substances
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Actins
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BGN protein, human
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Bgn protein, mouse
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Bgn protein, rat
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Biglycan
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Cdkn1b protein, mouse
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Extracellular Matrix Proteins
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Proteoglycans
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Angiotensin II
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Cyclin-Dependent Kinase Inhibitor p27
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cdk2 protein, mouse
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Cdk2 protein, rat
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Cyclin-Dependent Kinase 2
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Renin