Glycosaminoglycan Overproduction in the Aorta Increases Aortic Calcification in Murine Chronic Kidney Disease

BACKGROUND: Vascular calcification accompanying chronic kidney disease increases the mortality and morbidity associated with cardiovascular disorders, but no effective therapy is available. We hypothesized that glycosaminoglycans may contribute to osteoblastic differentiation of vascular smooth muscle cells during vascular calcification. METHODS AND RESULTS: We used exostosin‐like glycosyltranferase 2–deficient (EXTL2 knockout) mice expressing high levels of glycosaminoglycans in several organs including the aorta. We performed 5/6 subtotal nephrectomy and fed the mice a high‐phosphate diet to induce chronic kidney disease. Overexpression of glycosaminoglycans in the aorta enhanced aortic calcification in chronic kidney disease in EXTL2 knockout mice. Ex vivo and in vitro, matrix mineralization in aortic rings and vascular smooth muscle cells of EXTL2 knockout mice was augmented. Furthermore, removal of glycosaminoglycans in EXTL2 knockout and wild‐type mice‐derived vascular smooth muscle cells effectively suppressed calcium deposition in a high‐phosphate environment. CONCLUSIONS: These results illustrate an important role for glycosaminoglycans in the development of vascular calcification. Manipulation of glycosaminoglycan expression may have beneficial effects on the progression of vascular calcification in chronic kidney disease patients.