title: Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis.
abstract: OBJECTIVE
  Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet.
  
  
  RESULTS
  OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic β-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice.
  
  
  CONCLUSIONS
  OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice.
authors: Department of Medicine, Washington University in St Louis, MO 63110, USA.
authors: Jian-Su
authors: JS
authors: Shao
authors: Oscar L
authors: OL
authors: Sierra
authors: Richard
authors: R
authors: Cohen
authors: Robert P
authors: RP
authors: Mecham
authors: Attila
authors: A
authors: Kovacs
authors: James
authors: J
authors: Wang
authors: Kathryn
authors: K
authors: Distelhorst
authors: Abraham
authors: A
authors: Behrmann
authors: Linda R
authors: LR
authors: Halstead
authors: Dwight A
authors: DA
authors: Towler
references: Cardiovasc Res. 2009 Jan 1;81(1):178-86
references: 18852254
references: Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H428-34
references: 10666072
references: J Biol Chem. 2001 Apr 20;276(16):13065-71
references: 11278791
references: Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1209-17
references: 15863465
references: Nat Genet. 2000 Apr;24(4):391-5
references: 10742104
references: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):321-6
references: 19948844
references: Circ Res. 2010 Aug 20;107(4):485-94
references: 20576934
references: Cell Death Differ. 2010 Aug;17(8):1345-53
references: 20489730
references: J Biol Chem. 2008 Apr 11;283(15):9737-48
references: 18250169
references: Circulation. 2009 May 5;119(17):2305-12
references: 19380619
references: Hum Pathol. 2003 Apr;34(4):402-7
references: 12733123
references: Bone. 2004 Jan;34(1):13-25
references: 14751559
references: J Am Coll Cardiol. 2006 Apr 18;47(8):1707-12
references: 16631011
references: Circ Heart Fail. 2010 May;3(3):431-9
references: 20200330
references: Vasc Med. 2007 Nov;12(4):329-41
references: 18048471
references: J Am Soc Echocardiogr. 2002 Jul;15(7):708-14
references: 12094169
references: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1510-6
references: 16690876
references: J Histochem Cytochem. 1969 Feb;17(2):110-24
references: 4179464
references: Biomaterials. 2009 Sep;30(27):4676-86
references: 19520427
references: Dent Mater J. 2004 Dec;23(4):650-5
references: 15688734
references: J Biol Chem. 2000 Jun 30;275(26):20197-203
references: 10766759
references: Am J Med Genet A. 2006 Dec 1;140(23):2646-706
references: 17103447
references: Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):489-94
references: 12615658
references: Nat Rev Cancer. 2008 Mar;8(3):212-26
references: 18292776
references: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2589-96
references: 17932314
references: J Am Coll Cardiol. 2007 Jul 3;50(1):1-13
references: 17601538
references: Am J Pathol. 2002 Dec;161(6):2035-46
references: 12466120
references: Arthritis Rheum. 2009 Oct;60(10):2902-12
references: 19790060
references: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):290-5
references: 18006856
references: J Am Coll Cardiol. 2008 May 20;51(20):1967-74
references: 18482666
references: Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E207-14
references: 11739102
references: J Am Coll Cardiol. 2008 Sep 2;52(10):843-50
references: 18755348
references: Nature. 1997 Mar 6;386(6620):78-81
references: 9052783
references: Kidney Int. 2011 Feb;79(4):414-22
references: 20944546
references: J Leukoc Biol. 2006 Jul;80(1):59-65
references: 16684892
references: J Exp Pathol. 1986 Summer;2(4):261-73
references: 2946818
references: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):162-8
references: 19023094
references: Circ Res. 2006 Jun 23;98(12):1479-89
references: 16709900
references: J Clin Invest. 2003 Nov;112(9):1318-31
references: 14597759
references: Arterioscler Thromb Vasc Biol. 2006 May;26(5):1079-85
references: 16528009
references: Am J Pathol. 1996 Feb;148(2):569-77
references: 8579119
references: Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2302-9
references: 17717292
references: Exp Nephrol. 1999 Mar-Apr;7(2):103-13
references: 10213864
references: Arterioscler Thromb Vasc Biol. 2003 Jun 1;23(6):1029-34
references: 12730087
references: Circulation. 2008 Jan 22;117(3):411-20
references: 18172035
references: J Clin Invest. 2005 May;115(5):1210-20
references: 15841209
references: Circulation. 2008 Jun 3;117(22):2938-48
references: 18519861
references: J Biol Chem. 1998 Nov 13;273(46):30427-34
references: 9804809
references: J Vasc Surg. 2000 Feb;31(2):325-42
references: 10664501
references: Circ Res. 2010 Jul 23;107(2):271-82
references: 20489161
references: J Exp Med. 2002 Oct 21;196(8):1047-55
references: 12391016
references: Nat Protoc. 2009;4(12):1779-58
references: 19893510
references: Hypertension. 2010 Mar;55(3):579-92
references: 20101002
references: Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):978-83
references: 8696962
references: J Bone Miner Res. 2008 Nov;23(11):1798-805
references: 18597635
references: J Pathol. 2008 Mar;214(4):531
references: 18264996
references: Mol Diagn Ther. 2008;12(3):157-70
references: 18510379
references: J Thorac Cardiovasc Surg. 2010 Aug;140(2):305-312.e2
references: 20189193
references: Circulation. 2009 Apr 28;119(16):2209-16
references: 19364980
references: Circulation. 2006 May 2;113(17):2113-9
references: 16636166
references: J Bone Miner Res. 2008 Oct;23(10):1672-9
references: 18505371
references: Atherosclerosis. 2010 Dec;213(2):369-76
references: 20732681
references: J Cell Biol. 1997 Jun 2;137(5):1149-60
references: 9166414
references: Circulation. 2009 Apr 7;119(13):1785-94
references: 19307473
references: Circulation. 2007 Dec 11;116(24):2841-50
references: 18040026
references: J Biol Chem. 2007 Sep 7;282(36):26035-45
references: 17613532