Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth

Nicole Meyer,Désirée Nowak,Katja Woidacki,Jürgen Pollheimer,Philipp Velicky,Gudrun Meinhardt,Martin Knöfler,Ana C Zenclussen

doi:10.1038/srep45106

Nicole Meyer, Désirée Nowak + Show 6 more

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https://doi.org/10.1038/srep45106

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Abstract

Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling.

Highlights

Proteases secreted by MCs can be divided into carboxypeptidase A3 (Cpa3), tryptases and chymases; the latter are serine proteases that can be further divided into α- and β-chymases[14]
We found that Uterine natural killer cells (uNKs) were positive for mast cell protease (Mcpt)[5] in W-sh mice that are devoid of uterine mast cells (uMCs); these mice had an impaired spiral arteries (SA) shape[12] (Fig. S4)
In this study we found that the combined ablation of uNKs and uMCs on the one hand and the selective deletion of Mcpt5+ cells on the other hand dramatically impaired SA remodeling, which had detrimental consequences for fetal growth

Summary

Introduction

Proteases secreted by MCs can be divided into carboxypeptidase A3 (Cpa3), tryptases and chymases; the latter are serine proteases that can be further divided into α- and β-chymases[14]. Chymases degrade extracellular matrices[22,23], inhibit the proliferation of vascular SMCs24 and induce apoptosis in vascular SMCs22,25,26. These functions suggest a possible role of chymase during SA remodeling. We found that the combined absence of uNKs and uMCs substantially impaired SA remodeling and had detrimental consequences for fetal growth in contrast with no effect after NK depletion and a moderate effect in the absence of MCs. Further, we found that Mcpt5-expressing cells induce apoptosis of uterine SMCs (uSMCs) in the mouse system. CMA1 (human chymase)-expressing cells and human recombinant CMA1 increase the migration of invasive trophoblasts (EVTs) Both SMC apoptosis and increased EVT migration are reportedly important for SA remodeling. We detected uNKs as a previously unreported source for the chymase Mcpt[5]

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