title: Trophoblast- and vascular smooth muscle cell-derived MMP-12 mediates elastolysis during uterine spiral artery remodeling.
abstract: During the first trimester of pregnancy, the uterine spiral arteries are remodeled, creating heavily dilated conduits that lack maternal vasomotor control but allow the placenta to meet an increasing requirement for nutrients and oxygen. To effect permanent vasodilatation, the internal elastic lamina and medial elastin fibers must be degraded. In this study, we sought to identify the elastolytic proteases involved in this process. Primary first-trimester cytotrophoblasts (CTBs) derived from the placenta exhibited intracellular and membrane-associated elastase activity; membrane-associated activity was primarily attributable to matrix metalloproteinases (MMP). Indeed, Affymetrix microarray analysis and immunocytochemistry implicated MMP-12 (macrophage metalloelastase) as a key mediator of elastolysis. Cultured human aortic smooth muscle cells (HASMCs) exhibited constitutive membrane-associated elastase activity and inducible intracellular elastase activity; these cells also expressed MMP-12 protein. Moreover, a specific inhibitor of MMP-12 significantly reduced CTB- and HASMC-mediated elastolysis in vitro, to 31.7 ± 10.9% and 23.3 ± 8.7% of control levels, respectively. MMP-12 is expressed by both interstitial and endovascular trophoblasts in the first-trimester placental bed and by vascular SMCs (VSMCs) in remodeling spiral arteries. Perfusion of isolated spiral artery segments with CTB-conditioned medium stimulated MMP-12 expression in medial VSMCs. Our data support a model in which trophoblasts and VSMCs use MMP-12 cooperatively to degrade elastin during vascular remodeling in pregnancy, with the localized release of elastin peptides and CTB-derived factors amplifying elastin catabolism.
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, Manchester, United Kingdom. lynda.k.harris@manchester.ac.uk
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Harris
authors.forename: Samantha D
authors.initials: SD
authors.lastname: Smith
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Keogh
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Jones
authors.forename: Philip N
authors.initials: PN
authors.lastname: Baker
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
authors.forename: Judith E
authors.initials: JE
authors.lastname: Cartwright
authors.forename: Guy St J
authors.initials: GS
authors.lastname: Whitley
authors.forename: John D
authors.initials: JD
authors.lastname: Aplin
mesh_terms: D001011:Aorta / Q000166:cytology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003656:Decidua / Q000378:metabolism / Q000473:pathology; D004549:Elastin / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010196:Pancreatic Elastase / Q000378:metabolism; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000201:enzymology* / Q000473:pathology; D055988:Uterine Artery / Q000378:metabolism* / Q000473:pathology; D014599:Uterus / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D004549:Elastin; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12
references.citation: Am J Pathol. 2006 Apr;168(4):1134-47
references.pmid: 16565489
references.citation: Am J Obstet Gynecol. 1998 Mar;178(3):551-6
references.pmid: 9539525
references.citation: Science. 2002 Aug 16;297(5584):1186-90
references.pmid: 12183632
references.citation: Am J Pathol. 2006 Nov;169(5):1863-74
references.pmid: 17071607
references.citation: Endocrinology. 2009 Feb;150(2):1000-13
references.pmid: 18845641
references.citation: Circ Res. 2007 Mar 30;100(6):834-41
references.pmid: 17322170
references.citation: Exp Cell Res. 2003 Jul 15;287(2):314-24
references.pmid: 12837287
references.citation: J Pathol. 2006 Mar;208(4):535-42
references.pmid: 16402350
references.citation: Exp Cell Res. 2006 Apr 1;312(6):877-89
references.pmid: 16427620
references.citation: J Clin Invest. 1996 Dec 1;98(11):2572-9
references.pmid: 8958220
references.citation: Exp Cell Res. 2008 May 1;314(8):1765-76
references.pmid: 18394602
references.citation: Am J Pathol. 2009 May;174(5):1959-71
references.pmid: 19349361
references.citation: Biol Reprod. 2008 Jul;79(1):58-65
references.pmid: 18367676
references.citation: Atherosclerosis. 1999 Jul;145(1):97-106
references.pmid: 10428300
references.citation: Biochemistry. 2005 Mar 29;44(12):4636-47
references.pmid: 15779890
references.citation: J Pathol. 2005 Aug;206(4):476-85
references.pmid: 15940663
references.citation: Acta Anat (Basel). 1996;156(3):202-16
references.pmid: 9124037
references.citation: Am J Pathol. 2004 Jan;164(1):243-51
references.pmid: 14695337
references.citation: Blood. 2007 Oct 15;110(8):2916-23
references.pmid: 17606763
references.citation: Clin Exp Metastasis. 1998 Aug;16(6):489-500
references.pmid: 9872597
references.citation: Life Sci. 2000;67(10):1243-50
references.pmid: 10954057
references.citation: J Clin Invest. 2006 Mar;116(3):753-9
references.pmid: 16470245
references.citation: FASEB J. 2007 Jul;21(9):1968-78
references.pmid: 17341689
references.citation: Acta Obstet Gynecol Scand. 1998 Sep;77(8):808-13
references.pmid: 9776593
references.citation: Reprod Biol Endocrinol. 2004 Aug 04;2:59
references.pmid: 15294019
references.citation: J Biol Chem. 2005 May 20;280(20):19888-94
references.pmid: 15774480
references.citation: Placenta. 1996 Jul-Aug;17(5-6):269-75
references.pmid: 8829209
references.citation: Placenta. 2009 Jun;30(6):473-82
references.pmid: 19375795
references.citation: Placenta. 1983 Oct-Dec;4(4):397-413
references.pmid: 6634666
references.citation: Biol Reprod. 2003 Jul;69(1):1-7
references.pmid: 12620937
references.citation: Placenta. 2003 May;24(5):540-8
references.pmid: 12744931
references.citation: Placenta. 1998 May;19(4):241-52
references.pmid: 9639319
references.citation: J Biol Chem. 2006 Apr 21;281(16):11152-60
references.pmid: 16481329
references.citation: J Biol Chem. 1997 May 2;272(18):12189-94
references.pmid: 9115292
references.citation: J Biol Chem. 2002 Nov 22;277(47):44854-63
references.pmid: 12244048
references.citation: Mol Hum Reprod. 2002 Jun;8(6):559-65
references.pmid: 12029074
references.citation: Stem Cells. 2007 Nov;25(11):2777-85
references.pmid: 17641243
references.citation: Br J Obstet Gynaecol. 1986 Oct;93(10):1049-59
references.pmid: 3790464
references.citation: Am J Obstet Gynecol. 2003 Oct;189(4):1063-9
references.pmid: 14586356
references.citation: J Invest Dermatol. 2004 Feb;122(2):256-65
references.pmid: 15009703
references.citation: Acta Obstet Gynecol Scand. 1990;69(5):397-8
references.pmid: 2270764
references.citation: Nat Chem Biol. 2009 Sep;5(9):628-30
references.pmid: 19648933
references.citation: Biomedicine. 1977 Feb;26(1):48-52
references.pmid: 861345
references.citation: Lab Invest. 2001 Aug;81(8):1143-52
references.pmid: 11502865
references.citation: J Cell Sci. 1991 Aug;99 ( Pt 4):681-92
references.pmid: 1769999
references.citation: Reprod Sci. 2007 Dec;14(8 Suppl):28-34
references.pmid: 18089607
references.citation: Placenta. 2002 Feb-Mar;23(2-3):232-5
references.pmid: 11945091
references.citation: Reprod Fertil Dev. 2001;13(5-6):411-20
references.pmid: 11833938
references.citation: Cell Adhes Commun. 1994 Jul;2(3):185-93
references.pmid: 7827955
references.citation: Placenta. 2006 Sep-Oct;27(9-10):939-58
references.pmid: 16490251
references.citation: Mech Ageing Dev. 1990 Mar 1;52(1):61-70
references.pmid: 2156116
references.citation: Placenta. 1999 Mar-Apr;20(2-3):229-33
references.pmid: 10195746
references.citation: J Vasc Res. 1995 Mar-Apr;32(2):112-9
references.pmid: 7734657
references.citation: Cell Signal. 2005 May;17(5):571-80
references.pmid: 15683732
references.citation: J Pharmacol Exp Ther. 2003 Oct;307(1):429-36
references.pmid: 12954809
references.citation: J Biol Chem. 2006 Jan 6;281(1):151-7
references.pmid: 16286475
references.citation: J Pathol Bacteriol. 1967 Apr;93(2):569-79
references.pmid: 6054057
references.citation: J Clin Endocrinol Metab. 2004 Feb;89(2):812-22
references.pmid: 14764800
references.citation: FASEB J. 2005 Nov;19(13):1848-50
references.pmid: 16123172
references.citation: Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2871-7
references.pmid: 10591663
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):102-8
references.pmid: 15499040
references.citation: Br J Pharmacol. 1995 Dec;116(8):3099-109
references.pmid: 8719783
references.citation: Reprod Biomed Online. 2002;4 Suppl 3:14-7
references.pmid: 12470559
references.citation: Pathol Biol (Paris). 1998 Sep;46(7):517-26
references.pmid: 9842570
references.citation: Placenta. 2009 Jan;30(1):15-24
references.pmid: 19027158