Trophoblast- and vascular smooth muscle cell-derived MMP-12 mediates elastolysis during uterine spiral artery remodeling.
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.
Harris
Lynda K
LK
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
Smith
Samantha D
SD
Keogh
Rosemary J
RJ
Jones
Rebecca L
RL
Baker
Philip N
PN
Knöfler
Martin
M
Cartwright
Judith E
JE
Whitley
Guy St J
GS
Aplin
John D
JD
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
D015415:Biomarkers; D012333:RNA, Messenger; D004549:Elastin; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12
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