title: The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study.
abstract: Calcification and fibrointimal proliferation are associated with advanced complicated atherosclerosis in large arteries but may also occur in smaller vessels, resulting in ischaemic tissue necrosis. This study investigates whether the mechanisms of calcification and intimal fibrosis are similar in vessels of different sizes. The localization of osteopontin (OPN), matrix Gla protein (MGP), thrombospondin-1 (TSP-1), and cartilage oligomeric matrix protein (COMP) was investigated in three types of human vascular lesions: atherosclerosis, chronic vascular rejection (CVR) in renal allografts, and calcific uraemic arteriolopathy (calciphylaxis). These lesions were chosen as they affect different sized blood vessels and they exhibit a fibroproliferative intimal reaction, with or without calcification, resulting in luminal obliteration and ischaemic complications. OPN, MGP, TSP-1, and COMP were not detected in normal blood vessels. However, OPN and MGP were expressed at sites of calcification within atherosclerotic lesions and in microvessels in calciphylaxis, suggesting that calcification in different sized vessels may occur by a common mechanism. These proteins were not detected in areas of fibrointimal proliferation. In contrast, TSP-1 was localized primarily within the fibrous tissue of atherosclerotic lesions and was also expressed in the expanded fibrous intima of arteries showing CVR. COMP was localized primarily within the fibrous tissue under the lipid core of the majority of advanced atherosclerotic lesions. TSP-1 and COMP were also detected in areas of microcalcification in atherosclerotic lesions and TSP-1 was detected adjacent to areas of calcification in calciphylaxis. However, neither TSP-1 nor COMP was localized to calcific foci within these lesions. The localization of OPN, MGP, TSP-1, and COMP to pathological, but not normal arterial intima supports a pathogenetic role for these proteins in the development of vascular fibrosis and calcification. Modulation of their production and activity may offer a novel approach to the therapy of a number of vascular diseases.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, 2.205, Stopford Building, The University of Manchester, Manchester, UK. ann.canfield@man.ac.uk
authors.forename: A E
authors.initials: AE
authors.lastname: Canfield
authors.forename: C
authors.initials: C
authors.lastname: Farrington
authors.forename: M D
authors.initials: MD
authors.lastname: Dziobon
authors.forename: R P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: A M
authors.initials: AM
authors.lastname: Heagerty
authors.forename: S N
authors.initials: SN
authors.lastname: Kumar
authors.forename: I S D
authors.initials: IS
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta; D001161:Arteriosclerosis / Q000378:metabolism*; D002115:Calciphylaxis; D002135:Calcium-Binding Proteins / Q000032:analysis*; D064236:Cartilage Oligomeric Matrix Protein; D003331:Coronary Vessels; D016326:Extracellular Matrix Proteins / Q000032:analysis*; D005260:Female; D005355:Fibrosis; D006023:Glycoproteins / Q000032:analysis*; D006084:Graft Rejection / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016030:Kidney Transplantation; D008297:Male; D064235:Matrilin Proteins; D008875:Middle Aged; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000032:analysis*; D019700:Thrombospondin 1 / Q000032:analysis*; D014652:Vascular Diseases / Q000378:metabolism; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D053495:Osteopontin; D012795:Sialoglycoproteins; D019700:Thrombospondin 1; D000097568:Matrix Gla Protein; C506895:SPP1 protein, human; C577553:TSP5 protein, human