Simultaneous ablation of natural killer cells and mast cells leads to poor uterine vascularization that compromises fetal-well being.

Abstract

Abstract Once pregnancy is established, uterine spiral arteries (SA) need to undergo dramatic remodeling to ensure a consistent blood supply to the fetus. Here, we studied the single and joint participation of natural killer cells (NKs) and mast cells (MCs) in SA remodeling and pregnancy outcome and investigated the underlying mechanisms. We show that NK deficiency or their depletion arrested SA remodeling without affecting pregnancy. MC absence resulted in abnormally remodeled SAs and intrauterine growth restriction (IUGR). Combined absence of NKs and MCs dramatically affected SA remodeling, and impaired fetal growth. Despite abnormal Doppler measurements and dramatic IUGR, maternal maternal blood pressure was not affected. We found that a-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. We confirmed the importance of Mcpt5 by employing mice with selective deletion of Mcpt5+ cells: pregnant females presented un-remodeled SAs and growth-restricted progeny. The human a-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.