The cellular mechanisms of leukocyte-mediated decidual spiral artery remodelling

Abstract

A healthy human pregnancy requires transformation of the uterine spiral arterioles (SpA) in order to meet the increased demand of oxygen and nutrient supply to the developing fetus. Understanding SpA remodelling is important, as failure of this process is associated with serious consequences such as fetal growth restriction and/or preeclampsia. Remodelling of the SpA involves the loss of vascular smooth muscle and extracellular matrix (ECM) followed by colonisation of placentally-derived extravillous trophoblast (EVT). Recent studies have shown that decidual leukocytes, including decidual NK (dNK) cells and macrophages, infiltrate the SpA wall in the early stages of remodelling, prior to EVT invasion. We aimed to explore the signalling mechanisms for leukocyte infiltration into the SpA. Using explant cultures, in vitro studies and in situ observations we demonstrated that dNK cells and macrophages are recruited into the SpA in response to the CCL14 and CXCL6 released by activated endothelial cells. EVTs secreted factors, including IL-6 and CXCL-8, induced upregulation of these chemokines, identifying crosstalk between EVT and SpA endothelial cells as a trigger for immune cell recruitment. To investigate the temporal relationship of ECM degradation and leukocyte infiltration, detailed analysis of SpA in different stages of remodelling were carried out. Leukocyte infiltration coincided with the loss of ECM components such as collagen III, collagen IV, collagen VI, laminin, fibronectin and elastin. Global profiling of matrix metalloproteinases (MMP) in primary dNK cells and macrophages was carried out to identify the MMPs responsible for ECM loss during remodelling. We detected high mRNA and protein expression of MMP-2, -7, -9, -11, -16, -19 and TIMP-1, -2 and -3 in dNK cells and macrophages infiltrating the SpA. Interstitial EVTs (iEVT) and endovascular EVT (vEVT) are also rich in MMPs, expressing almost all MMPs. dNK cells and macrophages degraded gelatin through secretion of MMP-2 and MMP-9, and catabolised collagen in an in vitro model of the SpA. In situ zymography provided further supporting evidence of ECM proteolysis by dNK cells and macrophages around SpA in decidual basalis. In summary, we demonstrated vEVT crosstalk with SpA endothelium recruit decidual leukocytes into the SpA. These cells then initiate remodelling through MMP mediated ECM degradation before the arrival of EVTs. Decidual leukocytes therefore play a key role in regulating the critical process of uterine vascular transformation in early pregnancy.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Aplin (Supervisor), Lynda Harris (Supervisor) & Rebecca Jones (Supervisor)