Transformation of the Spiral Arteries in Human Pregnancy: Key Events in the Remodelling Timeline
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Placenta 32, Supplement B, Trophoblast Research, Vol. 25 (2011) S154eS158 Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta IFPA Gabor Than Award lecture: Transformation of the spiral arteries in human pregnancy: Key events in the remodelling timeline L.K. Harris* Maternal and Fetal Health Research Group, University of Manchester, UK article info abstract Article history: During human pregnancy, the uterine spiral arteries are progressively remodelled to form dilated Accepted 23 November 2010 conduits lacking maternal vasomotor control. This phenomenon ensures that a constant supply of blood is delivered to the materno-fetal interface at an optimal velocity for nutrient exchange. Conversion of Keywords: a tonic maternal arteriole composed of multiple layers of vascular smooth muscle, elastin and numerous Artery other extracellular matrix components, into a highly dilated yet durable vessel, requires tight regulatory Decidua control and the coordinated actions of multiple cell types. Initial disruption of the vascular wall, char- Elastin acterised by foci of endothelial cell loss, and separation and misalignment of vascular smooth muscle EVT fl Extracellular matrix cells (VSMC), is coincident with an in ux of uterine natural killer (uNK) cells and macrophages. uNK cells Invasion are a source of angiogenic growth factors and matrix degrading proteases, thus they possess the capacity Leukocytes to initiate changes in VSMC phenotype and instigate extracellular matrix catabolism. However, complete Macrophages vascular cell loss, mediated in part by apoptosis and dedifferentiation, is only achieved following colo- Myometrium nisation of the arteries by extravillous trophoblast (EVT). EVT produce a variety of chemokines, cytokines Remodelling and matrix degrading proteases, enabling them to influence the fate of other cells within the placental Trophoblast bed and complete the remodelling process. The complex interplay of cellecell and cellematrix inter- Uterine natural killer cells actions required for effective vascular transformation will be examined, with a particular focus on the Vascular smooth muscle cells role of (i) uNK cells and (ii) the enzyme matrix metalloproteinase-12 (MMP-12). Parallels with remod- elling events occurring in other vascular beds will also be drawn. Ó 2011 Published by IFPA and Elsevier Ltd. 1. Introduction muscle cells (VSMC) are replaced by EVT embedded in a fibrinoid- rich matrix, although re-endothelialization of these vessels occurs 1.1. Spiral artery remodelling involves a complex interplay of later in pregnancy. The vascular extracellular matrix (ECM) of the cellecell and cellematrix interactions spiral arteries, which provides mechanical strength, elasticity and structural support also undergoes substantial remodelling, altering Throughout gestation, the developing placenta competes with the mechanical properties of the vascular wall. maternal organs for the nutrients it requires for optimal growth Successful invasion is regulated by both maternal and fetal and function. To ensure that blood is delivered to the materno-fetal factors: EVT must invade the uterus to an adequate depth, and in interface without interruption, and at a velocity suitable for sufficient numbers to colonise the spiral arteries to the required nutrient exchange, the uterine spiral arteries are remodelled to degree. They must secrete the correct complement of proteases create heavily dilated conduits lacking maternal vasomotor control necessary to degrade the diverse ECM components in the vessel wall [1,2]. During the first twenty weeks of pregnancy, extravillous [3], and produce and respond to chemokines and cytokines that trophoblast (EVT) egress from placental villi and invade the allow them to communicate with the local decidual environment. decidual stroma, colonizing the spiral arteries from the outside in Maternal factors influencing successful colonisation include the (interstitial invasion), or migrate along the arterial lumens, colo- number of VSMC layers and deposition pattern of the ECM within the nizing the vessels from the inside out (endovascular invasion). spiral arteries, as a thicker vascular wall will require more effort to Subsequently, the endothelium and underlying vascular smooth remodel. Interestingly, first pregnancy results in irreversible modi- fication of medial elastin fibres which may promote vessel dilatation in future pregnancies [4]. The number of gap junctions and cell * Research (5th floor), St Mary’s Hospital, Oxford Road, Manchester, M13 9WL, fl UK. Tel.: þ44 161 7016962. adhesion molecules within the VSMC layers will in uence the ease E-mail address: [email protected]. by which EVT penetrate the vascular wall, and the level of expression 0143-4004/$ e see front matter Ó 2011 Published by IFPA and Elsevier Ltd. doi:10.1016/j.placenta.2010.11.018 L.K. Harris / Placenta 32, Supplement B, Trophoblast Research, Vol. 25 (2011) S154eS158 S155 of cell surface receptors for vasoactive factors will determine how disruption and endothelial cell loss [5]. uNK cells maintain a tran- VSMC respond to exogenous stimuli. sient contact with the vascular wall, departing before substantial Recent work by our laboratory has proposed that spiral artery loss of vascular cells has occurred, whereas macrophages remain in remodelling occurs via a coordinated series of events involving remodelling arteries for longer, perhaps contributing to tissue uterine natural killer (uNK) cells, macrophages and EVT [5]. Thus, to remodelling and clearance/phagocytosis of remnants of vascular adequately understand the processes involved, we must study (i) cells and ECM [11]. These observations have lead us to hypothesise how these different cell types interact with each other, and (ii) their that uNK cells secrete soluble factors that induce disruption and individual interactions with the ECM components within their local dedifferentiation of VSMC, resulting in vascular changes that prime environment. Much attention has been paid to the eventual fate the spiral arteries for colonisation by EVT. of the spiral artery VSMC [6e8], with rather less research dedicated to how remodelling is initiated, and how the vascular ECM is degraded. This review will primarily address uNK cell-VSMC 2.2. Soluble factors produced by uNK cells induce disruption of interactions and the evidence implicating uNK cells as mediators of spiral artery VSMC vascular remodelling. It will also discuss how EVT interact with the vascular ECM, and describe some of the physiological consequences To address this hypothesis, we obtained myometrial spiral of ECM remodelling. arteries from non-pregnant, pre-menopausal women undergoing hysterectomy for reasons such as fibroids, menorrhagia, ovarian cysts or familial risk of cancer. These arteries were incubated with 2. uNK cell-VSMC interactions uNK cell-conditioned medium (uNK-CM) prepared by isolating uNK cells from first trimester decidua by collagenase digestion and 2.1. Decidual leukocytes accumulate around remodelling arteries immuno-magnetic bead separation. Following 24 h in culture, uNK-CM was collected, centrifuged to remove cellular debris and It was first reported in 1998 that subtle changes in spiral artery stored at À20 C. In parallel, EVT were isolated from first trimester structure are observed in the secretory phase of the menstrual placentas by trypsin digestion and Percoll gradient centrifugation; cycle, and in the early pregnancy decidua prior to the arrival of EVT EVT-CM and medium from uNK-EVT co-cultures was collected in the [9]. These have since been termed trophoblast-independent or same manner. decidual-associated remodelling events [2,5], and include vasodi- Spiral arteries were cultured with unconditioned medium, uNK- latation, swelling or loss of the endothelium, disruption of VSMC CM, EVT-CM or uNK-EVT-CM for 72 h and were assessed for layers and vascular cell vacuolation. Early pregnancy is associated parameters of VSMC disruption. Whilst the majority of VSMC in þ with a dramatic influx of CD45 leukocytes into the decidua, which control arteries remained aligned in tightly packed layers (Fig. 1A), increase in number from approximately 8% in proliferative endo- arteries cultured with uNK-CM exhibited noticeable features of metrium to 23% in secretory endometrium, reaching 32% in first disruption (Fig. 1BeD) [12]. Firstly, a proportion of VSMC appeared trimester decidua [10]. Immunohistochemical analysis has identi- misaligned and had assumed positions perpendicular to the lumen, fied these cells as uNK cells and macrophages, and their pericellular rather than parallel to it. Secondly, some VSMC nuclei had changed and intramural accumulation directly correlates with VSMC from being long and thin to being rounded, as if altering their shape Fig. 1. uNK cell-conditioned medium induces disruption of spiral artery VSMC. Isolated spiral arteries were incubated with unconditioned medium (control; 20% (v/v)) or uNK-CM for 72 h. Transverse sections of OCT-embedded arteries were stained with propidium iodide (red). [A] VSMC in control arteries remained aligned in tightly packed layers. [B-D] Arteries cultured with uNK-CM exhibited [B] VSMC misalignment, [C] separation of VSMC layers and [D] rounding of VSMC nuclei. Scale bar 25 mm. S156 L.K. Harris / Placenta 32, Supplement B, Trophoblast Research, Vol. 25 (2011) S154eS158 or orientation within the vascular wall. Finally, VSMC layers were 3. EVT-ECM interactions beginning to separate in places,