Wednesday, June 1, 2016
Wednesday, June 1, 2016
Kenneth F. Trofatter, Jr., MD, PhDPregnancy and Childbirth

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 5 - Implantation and Placentation

Kenneth F. Trofatter, Jr., MD, PhD
Things have been so busy at work the last few weeks that it has been hard to find the time to write here, but I would like to finish up the series we started on plasminogen activator inhibitor-1 (PAI-1) and role in pregnancy outcome and recurrent pregnancy loss (RPL) before moving on to any other major topic. I will admit that the review of the literature on this topic has been somewhat tedious and at times confusing, but it has also been very educational from my own standpoint, and I figure, it’s okay to be a little selfish every once and awhile, especially if a few of our readers might also benefit from the results of the efforts. Anyway, in our last post we reviewed observations that have been made regarding the role of PAI-1 in ovulation and development (and regression) of the corpus luteum and posited possible deleterious effects on these events, under circumstances in which PAI-1 is elevated, that might lead to ovulatory defects and RPL in early pregnancy. Today we are going to turn our attention to observations that have been made regarding the role of PAI-1 in implantation and placentation.

During the first part of the menstrual cycle, prior to ovulation, the hormone that stimulates the growth and the development of the lining (endometrium) of the uterus is estrogen. As we discussed in our last post, following ovulation, the corpus luteum produces progesterone that prepares ('decidualizes') the endometrium to receive the fertilized egg; and, if implantation of the embryo occurs normally, the hormones (mostly hCG) that are produced by the developing placental tissues (trophoblast cells), stimulate the corpus luteum to continue to make progesterone until the placenta gets big enough to take over that function. In 1996, Lockwood and Schatz (J Soc Gynecol Investig 1996;3:159-65) reported that progesterone stimulation (decidualization) of estrogen-primed endometrial cells (estrogen up-regulates endometrial cell receptors for progesterone), both in vitro and in vivo, results in “a marked increase in the expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) and an inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA,respectively), matrix metalloproteinases (MMP), and endothelin-1 (ET-1) expression…” Thus, even prior to implantation, the fibrinolytic balance is shifted toward preservation of the extracellular matrix (ECM) structure and prevention of hemorrhage that could be imagined to occur as the embryo implants and the trophoblasts start eating their way into the maternal endometrium. Indeed, progesterone withdrawal shifts the fibrinolytic balance in the opposite direction and this is thought to be one of the factors that permits the shedding/bleeding from the endometrium with menstruation if pregnancy has not occurred successfully.

During the course of normal placentation, some trophoblasts invade the maternal endometrium to anchor the placenta, some migrate through the endometrium and then invade and remodel (open up) the maternal blood vessels (spiral arterioles) that will be the source of blood to the ‘placental bed’ from which the baby will extract oxygen and nutrients (and into which it will transfer its own waste products), and other trophoblasts develop into the frond-like villi that eventually dangle into the placental bed of maternal blood and actually perform these latter functions (transferring oxygen, nutrients, and wastes between the fetal and maternal circulations). Proliferating and invasive trophoblasts produce urokinase-like plasminogen activator (u-PA) and this helps to degrade the ECM and facilitates their migration within the endometrium. One of the primary roles of PAI-1 in normal placentation appears to be in controlling the degree to which trophoblastic cells actually invade the maternal tissues. Graham (Placenta 1997;18:137-43) found that a substance produced by maternal decidual cells, transforming growth factor-beta (TGF-beta), stimulates fetal trophoblasts to make both PAI-1 and the inhibitor of metalloproteinase-1 and also down-regulates trophoblast production of u-PA. This suggests that the trophoblasts, under the direction of maternal cells, may limit their own invasiveness by the secretion of these inhibitors that inactivate u-PA and prevent the degradation of the ECM.

This hypothesis is supported in a study by Floridan and colleagues (Placenta 2000;21:754-62). Beginning with the observation that “trophoblast invasion…in normal intrauterine pregnancies appears to be strictly regulated…whereas tubal and molar pregnancies seem to be characterized by uncontrolled excessive placental invasion,” PAI-1 localization was evaluated in both maternal and fetal tissues under these conditions. In normal pregnancies, PAI-1 was localized, predominantly to trophoblasts that were in closest proximity to maternal tissues: the basal plate of the placenta; the extravillous interstitial trophoblasts comprising the placental anchors in the endometrium; and the trophoblasts that replace maternal vascular endothelial cells as the result of the remodeling of the spiral arterioles. In the basal plate at the deepest layer of placental invasion, PAI-1 (secreted by the trophoblasts?) was noted to be associated with the surface membranes of maternal decidual cells “or confined to the extracellular matrix (ECM) facing the invasive front of anchoring villi.” In contrast, there was a paucity of PAI-1 expression by fetal trophoblasts and maternal cells in both tubal ectopic and molar pregnancies that accompanied uncontrolled trophoblast invasion and damage to maternal tissues.

So, if normal placental invasion of both the decidua and maternal spiral arterioles is at least partly the result of controlled and ‘normal’ expression of PAI-1 activity, we can easily speculate on the potential consequences of excessive PAI-1 production without defining the underlying cause. This could lead to very shallow invasion of the endometrium and inadequate migration to and invasion and remodeling of the spiral arterioles. If severe enough, this could result in early pregnancy loss and if less severe, could result in an abnormal placenta, typical of that seen in preeclampsia, accompanied by increased resistance to fetal and/or maternal perfusion and restriction of fetal growth.

There are many factors that might contribute to the increased expression of PAI-1 under these circumstances. In other posts we discussed the genetic polymorphisms such as 4G/4G that are associated with increased PAI-1 production and activity and this could possibly contribute from both the fetal and maternal sides. Since PAI-1 expression by trophoblasts is at least in part influenced by TGF-beta production by maternal decidual cells, then anything that contributed to increased TGF-beta production by either decidual cells, or cellular components of the maternal immune system, might also result in the fetal trophoblasts producing excessive PAI-1. Indeed, one could imagine that if an abnormal maternal immune response to the pregnancy, either innate or specific, was accompanied by the production of factors that up-regulated PAI-1 expression, this could also contribute to inhibition of trophoblast migration and invasion.

Personally, I believe that aberrations in the maternal immune response are a major cause of abnormalities of placentation that result in pregnancy loss and preeclampsia and there is some evidence indicating that modulation of PAI-1 expression is indeed one mechanism by which these deleterious affects are mediated. Bauer and colleagues (J Clin Endocrinol Metab 2004;89:812-22) reported that the cytokine, tumor necrosis factor (TNF) alpha, inhibits both invasion and migration of trophoblasts in tissue culture experiments. Furthermore, this inhibition is correlated with increased production of PAI-1 and can be reversed by specific antibodies against PAI-1, restoring normal trophoblast migration. In subsequent studies, Renaud and colleagues (Biol Reprod 2005;73:237-43) demonstrated that activated macrophages (components of the innate immune system) also inhibit trophoblast migration. They showed that this inhibition is clearly the result of TNF-alpha production by the macrophages, requiring specific binding of TNF-alpha to the trophoblasts, and that it is accompanied by decreased production of u-PA and increased production of PAI-1 by the trophoblasts themselves.

In our posts to this point, we have built the case that aberrations in the fibrinolytic balance, associated with increased production of PAI-1, accompany adverse pregnancy outcome both late in gestation and in early pregnancy, and have presented several mechanisms by which early pregnancy success might be impaired by increased PAI-1 expression. The questions then remain: can PAI-1 expression be down-regulated in individuals with increased PAI-1 and/or a genetic predisposition for the same and, if so, is this accompanied by improved pregnancy outcome? In our final installment in this series, we will present evidence that it can be and does!

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  • At Sun Nov 29, 11:42:00 AM 2009, Blogger sasquatchbaby said…

    I stumbled on this website and now have some questions. Me in a nutshell: I have a healthy 3 yo son. I had 2 mcs before him. He was conceived naturally and I had zero pregnancy issues. I did end up having an emergency c section because of "nonreassuring fetal trace". My husband and I starting ttc one year ago. I have had 5 mcs in that time. I was since diagnosed with: balanced translocation, MTHFH C677T single mutation (however, I have low homocysteine levels), PAI-1 4G/5G heterozygous. I learned of the balanced translocation after my 3rd miscarriage. It was recommended that we just keep trying...which we did. The PAI and MTHFR was just discovered. One doctor suggested that I take Lovenox at the start of the next pregnancy. One doctor suggested that I don't need the Lovenox. Bottom line: what should I do?

  • At Thu Dec 03, 09:25:00 AM 2009, Anonymous Anonymous said…

    I am hoping this website is just what I am looking for. My usual periods are extremely heavy, to the point where I have been prescribed a medication to help with it, my last period, five days ago, was very light and clottless..I went to the doctor who suspects pregnancy. He did a blood hcg test which results were 1.9 ( this testing was done three days after my "period") I am wondering if that is a normal reading so early on, and what your input is on the possiblity of being pregnant?


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