Transformation of the Spiral Arteries in Human Pregnancy: Key Events in the Remodelling Timeline

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 remodelling 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 modification 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 20 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, forming cracks or holes. VSMC disorganisation did not occur in a uniform manner throughout the 3.1. EVT mediate catabolism of the vascular extracellular matrix length of the artery; foci of disruption were evident in discrete regions of the vessel wall. Interestingly, spiral arteries cultured with The ability of EVT to transform the uterine spiral arteries is highly EVT-CM, or medium from uNK-EVT co-cultures exhibited levels of dependent on their capacity to remodel the vascular ECM. ECM VSMC disruption similar to those observed in control arteries. components present within the arterial wall include collagen IV, These observations suggest that: [1] uNK cells secrete a unique laminin, proteoglycans and elastic fibres, all of which are synthesised complement of soluble factors capable of destabilising the vascular by endothelial cells and VSMC. We have proposed that degradation architecture, providing them with the means to initiate spiral artery of elastin fibres within the arterial wall is the rate limiting step in the transformation, and [2] direct uNK e EVT cell interactions reduce remodelling process, as we believe that permanent vasodilatation the ability of uNK cells to induce vascular disruption. cannot be established without elimination of the stretch and recoil response. Whilst breakdown of other ECM components within the 2.3. Several uNK-derived factors may promote remodelling events spiral arteries is undoubtedly important, we have chosen to focus on the mechanisms of elastin catabolism. Interestingly, EVT can be A variety of vasoactive factors may be responsible for inducing observed migrating through breaks in the internal elastin lamina in VSMC disorganisation and vessel disruption. uNK cells isolated the first trimester placental bed [25], and EVT are able to degrade from first trimester decidua secrete angiopoietin-1, angiopoietin-2, elastin and phagocytose the resulting fragments in vitro [26]. interferon-g and vascular endothelial growth factor-C (VEGF-C) To identify the elastolytic proteases responsible, we performed [13,14], and unremodelled spiral arteries correspondingly express an elastase activity assay on trophoblast cell lysates in the presence VEGF receptor-2 and Tie2 [14]. uNK cells also produce matrix of several different broad spectrum protease inhibitors. We metalloproteinase-2 (MMP-2), MMP-7 and MMP-9 [5,11,15], which demonstrated that the majority of elastase activity was attributable degrade collagen IV, laminin and elastin and have been implicated to matrix metalloproteinases (MMP), rather than cathepsins, cas- as mediators of decidual vascular remodelling [5,11]. The ability of pases or urokinase plasminogen activator (uPA) [26]. Microarray uNK cells to promote trophoblast invasion via release of VEGF-A, analysis identified the most highly expressed mRNA transcripts in placental growth factor, interleukin-8, and interferon-inducible first trimester EVT as MMP-2 and MMP-12. Previous reports have protein-10 has recently been reported [16], and a role for uNK cell- described MMP-2 as an important mediator of trophoblast migra- derived VEGF-C in enhancing endovascular EVT function in vitro tion and invasion [27]; however, a role for MMP-12 in EVT function has also been described [17]. ELISA and multiplex assays have has never been described. confirmed that uNK-CM contains angiopoietin-1, angiopoietin-2, interferon-g, VEGF-C, MMP-2 and MMP-9 [13e15]; however, more 3.2. EVT-derived MMP-12 is a functional elastolytic protease work is required to investigate the ability of individual cytokines and growth factors to initiate vascular destabilisation. MMP-12, which is also named macrophage metalloelastase, is an extracellular zinc endopeptidase. It is synthesised as a 54 kDa 2.4. Trophoblast-independent remodelling events are observed in proenzyme, which is processed to liberate a 45 kDa NH2-terminal murine pregnancy active form, following loss of the pro-domain [28]. Successive processing releases the hemopexin domain and liberates the Trophoblast-independent alterations in spiral artery architec- 22 kDa mature form of MMP-12. Like other MMP, MMP-12 is ture are also observed in the mouse, both in pseudo-pregnancy, secreted as inactive zymogen, but in macrophages it can be acti- where the uterine arteries display an increased luminal diameter vated whilst still attached to the plasma membrane [29]. This and medial cross section [18], and throughout gestation, where finding also appears to hold true in trophoblasts, as elastase activity extensive vascular dilatation occurs despite minimal penetration of was localised to the plasma membrane in our experiments, rather the uterus by trophoblast [19]. In contrast to humans, spiral artery than the cytoplasm or the culture supernatants [26]. remodelling in the mouse is principally regulated by uNK cells. Immunohistochemistry was used to validate the microarray Remodelling fails to occur in mice deficient in uNK cells; however, data and confirm MMP-12 in isolated first trimester trophoblasts. reconstitution of the uNK cell population by bone marrow trans- Using an antibody that was specific for the catalytic domain, it was plantation [20], or administration of interferon-g [21] rescues this possible to demonstrate that active MMP-12 was present on the phenotype. These findings provide more evidence that uNK cells trophoblast cell surface. Furthermore, inclusion of a specific may contribute to remodelling events in the human placental bed. inhibitor of MMP-12 in the elastase activity assay reduced the activity of trophoblast lysates to approximately 40% of control 2.5. NK cells promote arterial remodelling in other vascular beds values, indicating that MMP-12 is functionally active. To determine whether MMP-12 is expressed in situ, first trimester placenta and Several studies have shown that peripheral blood NK (PBNK) cells, decidua from 8 to 12 weeks gestation was also immunostained. which are phenotypically distinct from uNK cells, mediate remod- MMP-12 expression was localised to the cytotrophoblast layer and elling events in a variety of vascular beds. Arteriogenesis was cell columns of first trimester placenta, and immuno-positive cells impaired in a mouse model of hind limb ischemia following PBNK cell were also observed in the villous stroma, likely corresponding to depletion [22], and atherosclerotic lesion size was reduced by 70% in placental macrophages (Hofbauer cells). In the decidua, stromal LDL receptor null mice following inactivation of PBNK cell function cells were positive for MMP-12, as was the vascular endothelium. [23]. Furthermore, in common with the early stages of spiral artery Both interstitial and endovascular EVT, identified using antibodies remodelling in pregnancy, where uNK cells assume a perivascular to cytokeratin-7 and HLA-G respectively, also expressed MMP-12. distribution [5], remodelling of mesenteric arteries in a mouse model MMP-12-positive VSMC were absent from intact arteries; however, of hypertension was associated with an influx of PBNK cells into the a subset of positive VSMC were observed in remodelling vessels. vessel wall [24]. Although their mechanism of action has not been This observation fits neatly with the finding that MMP-12 expres- addressed in detail, these data imply that NK cells have the ability to sion can be induced in isolated spiral artery segments following regulate many different aspects of vascular transformation. perfusion with trophoblast conditioned medium [26]. L.K. Harris / Placenta 32, Supplement B, Trophoblast Research, Vol. 25 (2011) S154eS158 S157

Our study has highlighted the important role of MMP-12 as may promote recruitment of leukocytes to the vascular wall. In a mediator of ECM remodelling in the placental bed, which may help addition, we believe that release of EDP may establish a positive to explain the basis of recent reports that both placental and decidual feedback loop which promotes EVT invasion, MMP-12 expression MMP-12 expression is altered in women with pre-eclampsia. A and activity and further elastin catabolism. dramatic downregulation of MMP-12 mRNA was noted in chorionic fi villus biopsies taken in the rst trimester of pregnancy from women 3.5. MMP-12 regulates leukocyte chemotaxis who went on to develop pre-eclampsia, compared to women who had a normal pregnancy outcome [30]. Similarly, MMP-12 expres- Other targets of MMP-12 include members of the ELR (þ)CXC sion was reduced in the decidua of women with pre-eclampsia at family of chemokines, namely CXCL-1, -2, -3, -5, and -8. MMP-12 delivery [31]. Although little is known about the precise actions of can also cleave and inactivate the monocyte chemotactic proteins MMP-12 in pregnancy, this enzyme has been shown to regulate CCL-2, -7, -8, and -13, in the process generating CCR antagonists. invasion, leukocyte chemotaxis, vascular remodelling in other Interestingly, a recent study demonstrated a significantly greater fi systems, suggesting that it may play an important role in the rst number of polymorphonuclear leukocytes and macrophages in the trimester placental bed. lungs of MMP-12 null mice than in their wild type counterparts, after administration of LPS [39], confirming that the proteolytic e 3.3. MMP-12 a key player in remodelling events? actions of MMP-12 can limit acute inflammatory responses in vivo. A number of the chemokines listed above are expressed by cells As well as being a potent elastolytic enzyme, MMP-12 is capable within the placental bed, thus their actions may also be regulated of degrading a diverse array of ECM components including type IV MMP-12 processing. CCL-7, a chemoattractant for uNK cells and fi collagen, laminin, bronectin, vitronectin and heparin sulphate macrophages is expressed in the first trimester decidua, along with proteoglycans. This makes it an ideal protease for mediating inva- CXCL1 [40]. CCL-8 is produced by uNK cells and is chemotactic for sion through the decidual stroma and colonisation of the arterial EVT [16], CCL-2 is produced by decidual leukocytes, and decidual wall. MMP-12 can activate pro-MMP-2 and pro-MMP-3 and can vascular cells express both CCL-2 and CXCL8 [40,41]. It is therefore process a1-anti-trypsin and latent transforming growth factor-b. possible that the actions of macrophage-derived MMP-12 limits Expression of MMP-12 in macrophages is upregulated by inter- leukocyte recruitment to the placental bed, by inactivating the feron-g and epidermal growth factor (EGF) [28]. As uNK cells in chemotactic stimuli that attracted them. Similarly, the arrival of human decidua are a potent source of interferon-g [13], and MMP-12-producing EVT in the walls of the spiral arteries may trophoblasts are a source of EGF [32], the potential for autocrine coordinate the withdrawal of perivascular leukocytes, via pro- and paracrine regulation of MMP-12 in the placental bed is evident. cessing of local chemoattractants. MMP-12 activity may also indirectly promote trophoblast invasion. It has been postulated that MMP can induce epithelial to mesenchymal transition by releasing bioactive ECM fragments and latent 3.6. MMP-12, angiogenesis and thrombosis growth factors, and by cleaving E-cadherin which results in fl increased b-catenin signalling [33]. As MMP-12 mediates autocrine MMP-12 is able to in uence angiogenesis and thrombosis by N-cadherin shedding from mouse aortic VSMC, which was associ- inactivating angiostatin, an inhibitor of angiogenesis, tissue factor ated with increased b-catenin signalling and proliferation [34], pathway inhibitor (TFPI) and urokinase plasminogen activator EVT-derived MMP-12 may promote VSMC disruption and dedif- receptor (uPAR). Tumour blood vessel density was increased in ferentiation by processing N-cadherin in the spiral arteries. MMP-12 null mice, in parallel with a reduction in the circulating levels of angiostatin [42], suggesting that MMP-12 activity can 3.4. MMP-mediated catabolism of elastin liberates chemotactic negatively regulate angiogenesis. Similarly, overexpression of MMP- peptides 12 in microvascular endothelial cells reduced angiogenesis in vitro by cleaving uPAR and disrupting its interactions with uPA, vitro- Recent research has demonstrated that catabolism of elastin by nectin and b-integrin, which are necessary for capillary morpho- MMP-7, MMP-9 or MMP-12 in vitro liberates a variety of small, genesis [43]. MMP-12 is also reported to cleave TFPI, which inhibits bioactive, elastin-derived peptides (EDP). Not only are these the tissue factor signalling pathway by binding to Factor Xa, gener- peptides chemotactic for neutrophils, fibroblasts, endothelial cells ating a procoagulant microenvironment. These observations suggest fl and monocytes, they have been shown to increase proliferation, that the capacity of MMP-12 to in uence the progression of spiral upregulate expression of MMP-1, MMP-2 and MT1-MMP and artery remodelling extends far beyond its ability to promote ECM induce elastin synthesis in different cell types [35]. A study of the breakdown and EVT invasion. factors regulating invasion of malignant glioma cells, which degrade the cerebral ECM and penetrate elastin-rich blood vessels 4. Summary in the brain, noted that proliferation, migration and MMP-12 expression were significantly enhanced by EDP [36]. Similar Transformation of the decidual and myometrial spiral arteries in observations hold true for melanoma cells: as well enhancing human pregnancy is regulated by a complex series of cellecell and proliferation, migration and invasion in vitro, and inducing a 3-fold celleECM interactions (Fig. 2). This review has highlighted the increase in tumour cell volume in vivo, EDP also promoted MMP-9 potential contributions of a single cell type e the uNK cell, and expression and collagen breakdown by tumour cells [37]. Process- a single protease e MMP-12. Evidence suggests that uNK cells ing of elastin by macrophage-derived MMP-12 and subsequent secrete soluble factors that induce disruption of VSMC architecture, release of EDP is believed to contribute to the development of effectively priming the spiral arteries for more efficient colonisa- emphysema: release of chemotactic EDP following catabolism of tion by EVT. The actions of MMP-12 within the placental bed are elastin in the lung leads to recruitment of monocytes, their differ- much less well understood, but likely influence the outcome of entiation into macrophages, further MMP-12-mediated elastin multiple remodelling events including ECM catabolism, tropho- catabolism and amplification of the pathology [38]. Taking all of blast invasion, VSMC phenotype and leukocyte recruitment. Whilst this information into account we hypothesise that bioactive prod- we are beginning to understand the intricate nature of these ucts of elastin catabolism released from remodelling spiral arteries events, there is still much more to learn. S158 L.K. Harris / Placenta 32, Supplement B, Trophoblast Research, Vol. 25 (2011) S154eS158

activity of human uterine NK cells at the maternal-fetal interface. J Immunol 2009;182:4085e92. [18] van der Heijden OW, Essers YP, Spaanderman ME, De Mey JG, van Eys GJ, Peeters LL. Uterine artery remodeling in pseudopregnancy is comparable to that in early pregnancy. Biol Reprod 2005;73:1289e93. [19] Leonard S, Murrant C, Taiyade C, van den Heuvel M, Watering R, Croy BA. Mechanisms regulating immune cell contributions to spiral artery modification e facts and hypotheses e a review. Placenta 2006;27(Suppl. A):S40e6. [20] Guimond MJ, Wang B, Croy BA. Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. J Exp Med 1998;187:217e23. [21] Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 2000;192:259e70. [22] van Weel V, Toes RE, Seghers L, Deckers MM, de Vries MR, Eilers PH, et al. Natural killer cells and CD4þ T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol 2007;27:2310e8. Fig. 2. Key events in the remodelling timeline. Initial remodelling events are mediated [23] Whitman SC, Rateri DL, Szilvassy SJ, Yokoyama W, Daugherty A. Depletion of by decidual leukocytes including uNK cells, which interact with [1] the vascular natural killer cell function decreases atherosclerosis in low-density lipopro- extracellular matrix (ECM) and [2] VSMC, as they cluster around the spiral arteries and tein receptor null mice. Arterioscler Thromb Vasc Biol 2004;24:1049e54. penetrate the vessel wall. Subsequent colonisation of the arteries by EVT, which may [24] Taherzadeh Z, VanBavel E, de Vos J, Matlung HL, van Montfrans G, Brewster LM, be aided by prior disruption of VSMC layers by the actions of uNK cells, brings the EVT et al. Strain-dependent susceptibility for hypertension in mice resides in the into close contact with the residual [3] ECM and [4] VSMC to allow completion of natural killer gene complex. Am J Physiol Heart Circ Physiol 2010;298:H1273e82. vascular transformation. [25] Crocker IP, Wareing M, Ferris GR, Jones CJ, Cartwright JE, Baker PN, et al. The effect of vascular origin, oxygen, and tumour necrosis factor alpha on trophoblast invasion of maternal arteries in vitro. J Pathol 2005;206:476e85. [26] Harris LK, Smith SD, Keogh RJ, Jones RL, Baker PN, Knofler M, et al. Tropho- Conflict of interest blast- and vascular smooth muscle cell-derived MMP-12 mediates Elastolysis during uterine spiral artery remodeling. Am J Pathol 2010;177:2103e15. The author would like to declare that there are no actual or [27] Staun-Ram E, Goldman S, Gabarin D, Shalev E. Expression and importance of fl matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast perceived con icts of interest associated with the publication of invasion. Reprod Biol Endocrinol 2004;2:59. this article. [28] Lagente V, Le Quement C, Boichot E. Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert Opin Ther Targets 2009;13:287e95. References [29] Cobos-Correa A, Trojanek JB, Diemer S, Mall MA, Schultz C. Membrane-bound FRET probe visualizes MMP12 activity in pulmonary inflammation. Nat Chem [1] Burton GJ, Woods AW, Jauniaux E, Kingdom JC. Rheological and physiological Biol 2009;5:628e30. consequences of conversion of the maternal spiral arteries for uteroplacental [30] Founds SA, Conley YP, Lyons-Weiler JF, Jeyabalan A, Hogge WA, Conrad KP. blood flow during human pregnancy. Placenta 2009;30:473e82. Altered global gene expression in first trimester placentas of women destined [2] Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human to develop preeclampsia. Placenta 2009;30:15e24. pregnancy: facts and controversies. Placenta 2006;27:939e58. [31] Lian IA, Toft JH, Olsen GD, Langaas M, Bjorge L, Eide IP, et al. Matrix metal- [3] Harris LK, Aplin JD. Vascular remodeling and extracellular matrix breakdown loproteinase 1 in pre-eclampsia and fetal growth restriction: reduced gene in the uterine spiral arteries during pregnancy. Reprod Sci 2007;14:28e34. expression in decidual tissue and protein expression in extravillous tropho- [4] Khong TY, Adema ED, Erwich JJ. On an anatomical basis for the increase in birth blasts. Placenta; 31: 615e620. weight in second and subsequent born children. Placenta 2003;24:348e53. [32] Matsuo H, Maruo T, Murata K, Mochizuki M. Human early placental tropho- [5] Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell blasts produce an epidermal growth factor-like substance in synergy with involvement in decidual spiral arteriole remodeling in early human preg- thyroid hormone. Acta Endocrinol 1993;128:225e9. nancy. Am J Pathol 2009;174:1959e71. [33] Orlichenko LS, Radisky DC. Matrix metalloproteinases stimulate epithelial- [6] Ashton SV, Whitley GS, Dash PR, Wareing M, Crocker IP, Baker PN, et al. mesenchymal transition during tumor development. Clin Exp Metastasis Uterine spiral artery remodeling involves endothelial apoptosis induced by 2008;25:593e600. extravillous trophoblasts through fas/fasl interactions. Arterioscler Thromb [34] Dwivedi A, Slater SC, George SJ. MMP-9 and -12 cause N-cadherin shedding Vasc Biol 2005;25:102e8. and thereby beta-catenin signalling and vascular smooth muscle cell prolif- [7] Harris LK, Keogh RJ, Wareing M, Baker PN, Cartwright JE, Aplin JD, et al. eration. Cardiovasc Res 2009;81:178e86. Invasive trophoblasts stimulate vascular smooth muscle cell apoptosis by a fas [35] Heinz A, Jung MC, Duca L, Sippl W, Taddese S, Ihling C, et al. Degradation of ligand-dependent mechanism. Am J Pathol 2006;169:1863e74. tropoelastin by matrix metalloproteinasesecleavage site specificities and [8] Keogh RJ, Harris LK, Freeman A, Baker PN, Aplin JD, Whitley GS, et al. Fetal- release of matrikines. FEBS J 2010;277:1939e56. derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha- [36] Coquerel B, Poyer F, Torossian F, Duliong V, Bellon G, Dubus I, et al. Elastin- related apoptosis-inducing ligand to induce smooth muscle cell death. Circ derived peptides: matrikines critical for glioblastoma cell aggressiveness in Res 2007;100:834e41. a 3-D system. Glia 2009;57:1716e26. [9] Craven CM, Morgan T, Ward K. Decidual spiral artery remodelling begins [37] Devy J, Duca L, Cantarelli B, Joseph-Pietras D, Scandolera A, Rusciani A, et al. before cellular interaction with cytotrophoblasts. Placenta 1998;19:241e52. Elastin-derived peptides enhance melanoma growth in vivo by upregulating the [10] Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lympho- activation of Mcol-A (MMP-1) collagenase. Br J Cancer 2010;103:1562e70. cytes in human endometrium: histochemical and immunohistochemical [38] Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, studies. Hum Reprod 1991;6:791e8. Marconcini LA, et al. Elastin fragments drive disease progression in a murine [11] Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular-leukocyte model of emphysema. J Clin Invest 2006;116:753e9. interactions: mechanisms of human decidual spiral artery remodeling in vitro. [39] Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific Am J Pathol 2010;177:1017e30. metalloelastase (MMP-12) truncates and inactivates ELR þ CXC chemokines and [12] Harris LK, Robson A, Lash GE, Aplin JD, Baker PN, Bulmer JN. Physiological generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in remodelling of the uterine spiral arteries during pregnancy: uterine natural terminating polymorphonuclear leukocyte influx. Blood 2008;112:3455e64. killer cells mediate smooth muscle cell disruption. Placenta 2010;31:A52. [40] Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA. Identification of [13] Lash GE, Robson SC, Bulmer JN. Functional role of uterine natural killer (uNK) chemokines important for leukocyte recruitment to the human endometrium cells in human early pregnancy decidua. Placenta 2010;31(Suppl. 1):S87e92. at the times of embryo implantation and menstruation. J Clin Endocrinol [14] Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, et al. Expression Metab 2004;89:6155e67. of angiogenic growth factors by uterine natural killer cells during early [41] Hannan NJ, Jones RL, White CA, Salamonsen LA. The chemokines, CX3CL1, pregnancy. J Leukoc Biol 2006;80:572e80. CCL14, and CCL4, promote human trophoblast migration at the feto-maternal [15] Naruse K, Lash GE, Innes BA, Otun HA, Searle RF, Robson SC, et al. Localization interface. Biol Reprod 2006;74:896e904. of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors for MMPs [42] Acuff HB, Sinnamon M, Fingleton B, Boone B, Levy SE, Chen X, et al. Analysis of (TIMPs) in uterine natural killer cells in early human pregnancy. Hum Reprod host- and tumor-derived proteinases using a custom dual species microarray 2009;24:553e61. reveals a protective role for stromal matrix metalloproteinase-12 in non-small [16] Hanna J, Goldman-Wohl D, Humana Y, Avraham I, Greenfield C, Natanson- cell lung cancer. Cancer Res 2006;66:7968e75. Yaron S, et al. Decidual NK cells regulate key developmental processes at the [43] Margheri F, Serrati S, Lapucci A, Chilla A, Bazzichi L, Bombardieri S, et al. human fetal-maternal interface. Nat Med 2006;12:1065e74. Modulation of the angiogenic phenotype of normal and systemic sclerosis [17] Kalkunte SS, Mselle TF, Norris WE, Wira CR, Sentman CL, Sharma S. Vascular endothelial cells by gaineloss of function of pentraxin 3 and matrix metal- endothelial growth factor C facilitates immune tolerance and endovascular loproteinase 12. Arthritis Rheum 2010;62:2488e98.