I-6: Remodelling Uterine Spiral Arteries inPregnancy
نویسنده
چکیده مقاله:
Background: During the first trimester of pregnancy the uterine spiral arteries that supply blood to the placenta are remodelled, creating heavily dilated conduits lacking maternal vasomotor control. To effect permanent vasodilatation, the internal elastic lamina and medial elastic fibres must be degraded. Failure of remodelling is a key characteristic of the pathological placenta and is thought to be a primary causative mechanism in pre-eclampsia and fetal growth restriction. We sought to identify the elastolytic proteases involved and their source. Maternal (vascular smooth muscle cells, uterine NK cells and macrophages) and fetal (extravillous trophoblast) cells are all potentially involved in ECM remodelling. Materials and Methods: We examined cells in situ in vessel walls at various stages of transformation, and used a combination of in vitro methods to specify and test molecular mechanisms.Results: Primary first trimester cytotrophoblasts (CTB) derived from the placenta exhibited intracellular and membrane-associated elastase activity; membrane-associated activity was primarily attributable to matrix metalloproteinases (MMP). Affymetrix microarray analysis and immunocytochemistry implicated MMP-12 (macrophage metalloelastase) as a key mediator of elastolysis. Cultured human aortic smooth muscle cells (HASMC) exhibited constitutive membrane-associated elastase activity and inducible intracellular elastase activity, and also expressed MMP-12 protein. A specific inhibitor of MMP-12 significantly reduced CTB- and HASMCmediated elastolysis in vitro. MMP-12 is expressed by interstitial and endovascular trophoblast in the first trimester placental bed and by vascular SMC (VSMC) in remodelling spiral arteries. Perfusion of isolated spiral artery segments with CTB-conditioned medium stimulated MMP-12 expression in medial VSMC.Conclusion: These data support a model in which trophoblast and VSMC utilize MMP-12 cooperatively to degrade elastin during vascular remodelling in pregnancy, with the localized release of elastin peptides and CTB-derived factors amplifying elastin catabolism. Other evidence indicates that maternal uNK cells and macrophages also contribute to elastin degradation and vessel wall disruption.
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عنوان ژورنال
دوره 4 شماره 2
صفحات 6- 6
تاریخ انتشار 2010-05-01
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