The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell. Versican interacts with hyaluronan, a long chain glycosaminoglycan, to create expanded viscoelastic pericellular matrices that are required for arterial smooth muscle cell (ASMC) proliferation and migration. Versican is also prominent in advanced lesions of atherosclerosis, at the borders of lipid-filled necrotic cores as well as at the plaque-thrombus interface, suggesting roles in lipid accumulation, inflammation, and thrombosis. Versican influences the assembly of ECM and controls elastic fiber fibrillogenesis, which is of fundamental importance in ECM remodeling during vascular disease. Collectively, these studies highlight the critical importance of this specific ECM component in atherosclerosis and restenosis.

Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican

Elastic fibres and vascular structure in hypertension

Costello syndrome (CS) is a rare congenital anomaly syndrome. Although it may be classified as an "overgrowth" syndrome due to slightly increased birth weight and relative macrocephaly, it is characterized by severe postnatal failure to thrive and short stature. Patients with CS have an increased risk for malignant tumors, a hallmark of several model overgrowth syndromes. The most common tumor in CS is rhabdomyosarcoma (RMS), followed by neuroblastoma and bladder carcinoma. The occurrence of bladder carcinoma in adolescents is distinctly unusual as this is typically a neoplasm of older adults and is not seen with increased frequency in other tumor predisposition syndromes. The increased tumor frequency in CS led to the proposal of a screening protocol, consisting of abdominal and pelvic ultrasounds, and urine studies for catecholamine metabolites and hematuria. It has since become apparent that patients with CS have an increased excretion of catecholamine metabolites in urine without the presence of an identifiable catecholamine secreting tumor. Thus, the urine assay for catecholamines is unhelpful as a screening test for neuroblastoma and should not be used in this population. The benefit of abdominal and pelvic ultrasound and urinalysis for hematuria as screening tests remains to be shown. A timely diagnosis of CS is a necessary prerequisite for awareness of the increased tumor risk. Once a malignancy has been identified, treatment should follow standard protocols. Additional medical problems characteristic for CS, such as hypertrophic cardiomyopathy and arrhythmia, need to be considered and addressed appropriately.

Tumor predisposition in Costello syndrome

Versican and the control of inflammation.

Provisional matrix: A role for versican and hyaluronan

The phenotypic resemblance of patients with Costello syndrome and Hurler disease has been linked to impaired formation of elastic fibers that coincides with elevated cellular proliferation. Impaired elastogenesis in these diseases associates with respective abnormal accumulation of chondroitin sulfate and dermatan sulfate proteoglycans that induce cell surface shedding of elastin-binding protein (EBP) normally required for intracellular chaperoning of tropoelastin and its assembly into elastic fibers. A variant of the chondroitin sulfate proteoglycan versican, V3, which lacks chondroitin sulfate, has recently been shown to stimulate elastic fiber assembly and decrease proliferation when expressed by retroviral transduction in arterial smooth muscle cells. However, the mechanism(s) by which V3 influences this phenotype is not known. We now demonstrate that transduction of skin fibroblasts from Costello syndrome and Hurler disease patients with cDNA to versican V3 completely reverses impaired elastogenesis and restores normal proliferation of these cells. This phenotypic reversal is accompanied by loss of chondroitin sulfate from the cell surface and increased levels of EBP. Versican V3 transduction of skin fibroblasts from GM 1 -gangliosidosis patients, which lack EBP, failed to restore impaired elastogenesis. These results suggest that induction of elastic fiber production by gene transfer of versican V3 in skin fibroblasts is mediated by rescue of the tropoelastin chaperone, EBP.

Retrovirally Mediated Overexpression of Versican V3 Reverses Impaired Elastogenesis and Heightened Proliferation Exhibited by Fibroblasts from Costello Syndrome and Hurler Disease Patients

Kela Liu

Papers

Retrovirally Mediated Overexpression of Versican V3 Reverses Impaired Elastogenesis and Heightened Proliferation Exhibited by Fibroblasts from Costello Syndrome and Hurler Disease Patients