Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth.
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.
Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Nicole
N
Meyer
Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Katja
K
Woidacki
Dept. of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, Vienna, Austria.
Martin
M
Knöfler
Dept. of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, Vienna, Austria.
Gudrun
G
Meinhardt
Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Désirée
D
Nowak
Dept. of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, Vienna, Austria.
Philipp
P
Velicky
Dept. of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, Vienna, Austria.
Jürgen
J
Pollheimer
Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
Ana C
AC
Zenclussen
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D001794:Blood Pressure; D053818:Chymases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D047109:Fetal Development; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics
D015415:Biomarkers; C509227:Cma1 protein, mouse; C509226:CMA1 protein, human; D053818:Chymases