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.

HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia

“…S1B). MMP12 is a metalloelastase and has been implicated in human trophoblastdirected uterine spiral artery remodeling (30,34). We used the overlap of in vitro and in vivo profiles and the conservation in rat and human placentation to guide our analysis, which led to a focus on MMP12.…”

“…Structural changes associated with tissue plasticity are engineered via activation of matrix metalloproteinases (MMPs) (27,28). MMPs are responsive to environmental signals and promote the movement of cells through tissue matrices, facilitate structural changes in blood vessel integrity, and contribute to morphogenesis of the placenta (18,27,(29)(30)(31).…”

The content of matrix metalloproteinase-12 in pregnancy complicated by preeclampsia

“…В экспериментах in vitro L.K. Harris et al было показано, что ММР-12 секретируется клетками трофобласта, при-нимает активное участие в процессе деграда-ции эластина стенок спиралевидных маточных артерий [14]. Как извест но, «недостаточная» перестройка стенок спиралевидных маточ-ных артерий приводит к изменению строения и функционирования плаценты на протяжении всей беременности [3].…”

“…Большое внимание исследователей уделяется ММП 2-го и 9-го ти-пов, показана их роль при беременности: они определяют ход имплантации, плацентации, влияют на инвазивную способность трофобла-ста в эндометрии [9][10][11]. Относительно ММП-12 в литературе имеются единичные исследова-ния, посвященные изучению при беременно-сти [12][13][14]. Изучение концентрации ММП-12 при беременности позволит определить ее возможную роль в развитии преэклампсии.…”

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion

“…Matrix metalloproteinase 12 or macrophage elastase is also expressed by both the endometrium and trophoblast. Major sources of MMP12 are uterine natural killer cells and macrophages [43], interstitial and endovascular trophoblasts, as well as vascular smooth muscle cells [44]. The MMP12 is a key mediator of elastolysis and contributes to the remodeling of spiral arteries.…”