Proceedings of The Physiological Society
University of Manchester (2010) Proc Physiol Soc 19, C42
Physiological remodelling of the uterine spiral arteries during human pregnancy: uterine natural killer cells mediate smooth muscle cell disruption
L. K. Harris1, A. Robson2, G. E. Lash2, J. D. Aplin1, P. N. Baker3, J. N. Bulmer2
1. Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom. 2. School of Surgical and Reproductive Sciences, University of Newcastle, Newcastle, United Kingdom. 3. Department of Obstetrics & Gynaecology, University of Alberta, Edmonton, Alberta, Canada.
During the first twenty weeks of pregnancy, the uterine spiral arteries are remodelled to form highly dilated channels that lack maternal vasomotor control. This process facilitates delivery of blood to the placenta at an optimal velocity and pressure for nutrient exchange. The early stages of arterial remodelling are characterised by a dramatic disruption of medial vascular smooth muscle cell (VSMC) layers, which is coincident with an influx of uterine natural killer (uNK) cells . Subsequently, extravillous trophoblast cells (EVT) derived from the placenta colonise the vascular wall, replacing both the endothelium and the VSMC. We hypothesised that soluble factors secreted by uNK cells induce VSMC disorganisation and dedifferentiation, facilitating entry of EVT. Unremodelled myometrial spiral arteries were obtained from non-pregnant, pre-menopausal women undergoing hysterectomy. Primary uNK cells and EVT were isolated from first trimester decidua and placenta obtained at surgical termination of pregnancy. Twenty four hours after isolation, conditioned medium (CM) was collected from uNK cells, EVT and uNK-EVT co-cultures. Spiral arteries were cultured with CM for up to 96h to mimic the early pregnancy environment; a subset of vessels was pre-treated with uNK-CM for 48h and then co-cultured with EVT. VSMC in arteries cultured with uNK-CM (20% (v/v)) for 48h or more displayed reduced α-smooth muscle actin immunoreactivity consistent with dedifferentiation, became misaligned with the appearance of spaces between layers, and showed altered nuclear morphology, when compared to arteries cultured with control CM, EVT-CM or uNK-EVT co-culture CM (n=10; P<0.001; Kruskal Wallis test). VSMC disruption was localised to discrete areas of the vessel wall and did not cause a significant change in mean arterial diameter or medial area. When seeded onto the interstitial surface of spiral arteries, EVT colonised the mural tissue after 48h, although the number of invading cells was low within this timeframe. Pre-treatment of arteries with uNK-CM did not increase the number of EVT colonising the vessels; however, the area of the arterial wall exhibiting VSMC disruption was increased, compared to arteries pre-treated with control CM (n=5; P<0.05; Kruskal Wallis test). We conclude that soluble factors secreted by uNK cells induce focal disorganisation and dedifferentiation of VSMC within uterine spiral arteries, initiating mural disruption prior to colonisation by EVT. As suggested by previous histological analysis , strict spatio-temporal regulation of remodelling events is critical, as uNK - EVT interactions reduced the ability of uNK cells to produce vasoactive factors.
Where applicable, experiments conform with Society ethical requirements