Differential Expression of Growth-, Angiogenesis- and Invasion ...

■ REVIEW ARTICLE ■

DIFFERENTIAL EXPRESSION OF GROWTH-, ANGIOGENESIS- AND INVASION-RELATED FACTORS IN THE DEVELOPMENT OF PLACENTA ACCRETA Jenn-Jhy Tseng1,2,3*, Min-Min Chou1,2,4 1

Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Hung-Kuang University, Taichung, 3Institute of Clinical Medicine, National Yang-Ming University, Taipei, and 4 Chung-Shan Medical University, Taichung, Taiwan.

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SUMMARY Placenta accreta is the major cause of maternal death complicated by massive peripartum hemorrhage. Its development is traditionally considered to be related to a decidual defect caused by previous cesarean deliveries or uterine curettages. Usually, placental villi firmly adhere to the superficial myometrium and deeply invade, or even penetrate, the uterine wall. Abnormal uteroplacental neovascularization is another characteristic. Therefore, we hypothesized that placenta accreta develops as a result of abnormal expressions of growth-, angiogenesis- and invasion-related factors in trophoblast populations. We have found, in pregnancies complicated by placenta accreta: upregulated epidermal growth factor receptor and downregulated c-erbB-2 oncoprotein in syncytiotrophoblasts; downregulated vasculoendothelial growth factor receptor-2 expression in syncytiotrophoblasts and increased vasculoendothelial growth factor in placental lysates; and downregulated Tie-2 expression in syncytiotrophoblasts and enhanced angiopoietin-2 level in placental lysates. However, matrix metalloproteinase expression was not upregulated, so the association of these invasion-related molecules with placenta accreta is less likely. Taken together, these findings imply that complex factors, either alone or in combination, might be responsible for the development of placenta accreta. Further studies are needed to understand the signaling pathways and possible genetic events. [Taiwanese J Obstet Gynecol 2006;45(2):100–106] Key Words: angiogenesis, growth, invasion, placenta accreta, trophoblast

Introduction Placenta accreta is strongly related to antepartum and postpartum hemorrhage. Based on the depth of trophoblast invasion and disease severity, it may include placenta accreta vera, placenta increta, and placenta percreta. The prenatal diagnosis is aided by a combination of grayscale and color Doppler ultrasonography [1]. Although the pathogenesis of placenta accreta is characterized at the microscopic (poor decidualization with intramyometrial infiltration of the villous tissues)

*Correspondence to: Dr Jenn-Jhy Tseng, Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, 160, Section 3, Taichung-Kang Road, Taichung 40705, Taiwan. E-mail: [email protected] Accepted: February 14, 2006

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and macroscopic (profuse uteroplacental neovascularization in the region of interest) levels, there have been few reports on the molecular milieu of this disorder [2,3]. Earl et al published an immunohistochemical study of four cases using antibodies against cell membrane antigens, placental hormones, and cytokeratins [2]. They concluded that placenta accreta is not associated with increased capacity for proliferation or invasiveness in trophoblast populations. Further, Hochner-Celnikier et al investigated four factors indicative of trophoblast invasiveness in 20 cases and concluded that the pathogenesis of placenta accreta is not related to overinvasiveness of the trophoblasts [3]. The modulation of trophoblast migration and invasion during normal placental development is interdependently influenced by different kinds of molecules, Taiwanese J Obstet Gynecol • June 2006 • Vol 45 • No 2

Molecular Aspects of Placenta Accreta

such as growth factors and their receptors, cytokines, hormones, adhesion molecules, and enzymes, in an autocrine or paracrine manner [4–6]. Through tight spatial and temporal regulation, placental villi do not proceed beyond the inner third of the myometrium [7–9]. Clinically, loss of balance between trophoblast invasion and the maternal decidual defense barrier may result in preeclampsia and intrauterine growth retardation (IUGR) (under-invasion) or gestational trophoblastic disease and placenta accreta (over-invasion) [10–12]. Decidual maldevelopment in placenta accreta, a common histologic finding, is usually caused by previous cesarean sections or uterine curettages. Due to the decreased production of tissue inhibitor of metalloproteinase (TIMP) and transforming growth factor-␤ resulting from decidual defects, the proliferation, migration, and invasiveness of trophoblast populations might be changed significantly [13,14]. In contrast, an in vitro co-culture study showed no significant increase in cytotrophoblast invasion even without a decidual endothelial cell monolayer [15]. Clearly, in addition to the well-known risk factor of decidual maldevelopment, the regulatory factors influencing the occurrence of placenta accreta are complex and need to be elucidated. Therefore, we hypothesized that the pathogenesis of placenta accreta involves abnormal expression of growth-, angiogenesis- and invasion-related factors in trophoblast populations.

Epidermal Growth Factor Receptor and c-erbB-2 Oncoprotein Trophoblast invasion during human placentation is a highly complicated process involving cellular proliferation, migration and differentiation. Tyrosine kinase receptors are known to be involved in these processes. Epidermal growth factor receptor (EGFR) and the c-erbB-2 oncoprotein are structurally and functionally related tyrosine kinase receptors, expressed in high amounts in human placenta [5]. We demonstrated using immunohistochemistry that expression of EGFR in the syncytiotrophoblast was significantly higher in cases than controls (p ⫽0.03), while the immunoreactivity of c-erbB-2 was significantly lower in cases than controls (p < 0.001). However, no significant difference in the expression of EGFR and c-erbB-2 in the villous and extravillous cytotrophoblastic cells was noted between cases and controls. Western blot analyses showed an increase in EGFR expression in three of four placenta accreta specimens compared with normal placental tissues from the same trimester [16]. Taiwanese J Obstet Gynecol • June 2006 • Vol 45 • No 2

Vasculoendothelial Growth Factor, Placenta Growth Factor, and Their Receptors Vasculoendothelial growth factor (VEGF), placenta growth factor (PlGF), and their receptors (VEGFR-1, -2 and -3) are well-known angiogenic factors [17–21]. VEGF, VEGF-B and PlGF bind to VEGFR-1/Flt-1; VEGF and VEGF-C bind to VEGFR-2/KDR; and VEGF-C binds to VEGFR-3/Flt-4 [22–26]. During normal pregnancy, the expression of VEGF and its receptors in the trophoblasts regulates the secretion of a wide range of proteins and hormones [18,27]. Soluble isoforms of VEGFR, sVEGFR-1 and sVEGFR-2 regulate the biological activities of PlGF and VEGF [28,29]. Accumulating evidence indicates that these proteins are involved in the pathogenesis of placental disorders. In hypoxic/ ischemic regions of pathologic placentas, expression of PlGF and VEGFR-1 is enhanced in villous trophoblasts via autocrine regulation, whereas expression of VEGF and VEGFR-2 is increased within the villous vessels through paracrine regulation [21]. Villi from missed abortion and blighted ovum show diminished immunoreactivity of VEGF in the trophoblasts, VEGFR-1 in the syncytium, and VEGFR-2 in the trophoblasts [30]. Furthermore, increased VEGFR-1 expression in the trophoblasts from pregnancies complicated by preeclampsia and IUGR indicates abnormal placental function and hypoxia [31]. Increased sVEGFR-1 might explain the low PlGF concentrations found in preeclamptic subjects [31,32]. We have shown that VEGFR-2 expression in syncytiotrophoblast, rather than villous and extravillous cytotrophoblasts, is significantly lower in cases than controls in both the second and third trimesters (p ⫽0.005 and 0.002, respectively) [33]. However, expression of VEGFR-1 and VEGFR-3 in trophoblast populations was not significantly different in controls and cases (p > 0.05). Endothelial cells of the larger vessels in specimens from placenta accreta stained stronger for Ki-67 (a proliferating cell nuclear antigen marker) than those from normal placenta. Western blot analyses and reverse transcription polymerase chain reaction (RT-PCR) showed that VEGFR-2 expression correlated with the trend in immunohistochemical data (p < 0.05). Furthermore, enzyme-linked immunosorbent assay (ELISA) on the placental lysates showed that women with placenta accreta had significantly higher VEGF (p ⫽ 0.001) and lower sVEGFR-2 concentrations (p ⫽0.015) than those with normal pregnancy. However, PlGF and sVEGFR-1 concentrations did not show a dramatic difference between cases and controls (p ⫽0.149 and 0.354, respectively). 101

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Consensus exists that VEGF family molecules are important for both nonendothelial and endothelial effects in physiologic and pathologic processes [31,34,35]. In our study, VEGFR-2 in cases complicated by placenta accreta showed significantly lower expression in the syncytiotrophoblast, which may indirectly depress the effects of human chorionic gonadotropin and human placental lactogen on trophoblast invasion and angiogenesis [36–38]. Therefore, decreased VEGFR-2 expression is probably not a change specific to placenta accreta, but is associated with the fine balance between expression of pro- and anti-invasive factors within the decidual layer and uterine myometrium to regulate the depth and rate of placental invasion. The impact of the reduction of membrane-bound VEGFR-2 on placenta accreta remains to be elucidated. sVEGFR-1, which antagonizes VEGF function, has been implicated in the pathophysiology of preeclampsia [39,40]. Similar to sVEGFR-1, sVEGFR-2 has regulatory consequences with respect to VEGF-mediated angiogenesis as well as the potential to serve as a quantitative biomarker of angiogenesis [29]. In addition, the isolated sVEGFR-2 fragment can inhibit tumor angiogenesis in vivo [41]. Increased VEGF together with decreased sVEGFR-2 placental concentrations imply paracrine induction of neovascularization during the development of placenta accreta. The stronger immunohistochemical expression of Ki-67 in endothelial cells of larger blood vessels might further support the potential actions of VEGF on the development of the uteroplacental neovascularization typical of placenta accreta.

Angiopoietins and Receptors Although the role of the angiopoietin/Tie receptor system in vasculogenesis and angiogenesis has been previously investigated, little is known about its role in diseases other than malignancies [42]. Tie-1 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) and Tie-2 (tunica internal endothelial cell kinase) receptors have been regarded as specific vascular endothelial markers [43]. The ligand for Tie-1 has not been identified, and it is unclear whether Tie-1 is functionally similar to Tie-2 [44]. Tie-2 has three known ligands: angiopoietin-1 (Ang-1), Ang-2, and Ang-4 [45]. In situ hybridization studies have detected Ang-1 and Tie-2 in the trophoblast bilayer of a first-trimester placenta, whereas Ang-2 mRNA is restricted to the cytotrophoblast, suggesting that they have a role in trophoblast function during early embryonic development (e.g., nitrous oxide release and

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trophoblast migration) [46]. These data imply a specific role for Ang-1, Ang-2, and their receptor Tie-2 in normal and pathologic human placentas. Pertubation of this would result in acute and chronic changes in placental vascular structure and trophoblast function, such as IUGR, preeclampsia, and recurrent abortion [30,47–49]. We have found that immunohistochemical expression of Tie-2 in syncytiotrophoblast, rather than in cytotrophoblastic and extravillous trophoblastic cells, is significantly lower in cases than controls (p ⫽0.015 and 0.025, respectively) [50]. Decreased expression of Tie-2 protein is observed by Western blot analysis in placental accreta specimens compared with tissue from normal placentas from the same trimester (p < 0.05). These results are similar to the trends of immunohistochemical results in syncytiotrophoblasts. However, there is no obvious trend in Tie-1 protein expression between cases and controls (p > 0.05). ELISA in the placental lysates reveals significantly higher Ang-2 (p ⫽0.026) and lower Tie-2 concentrations (p ⫽0.003) in women with placenta accreta than those with a normal pregnancy. However, there is no significant difference in Ang-1 placental levels between the groups (p ⫽0.260). Furthermore, Ang-2 shows a higher expression in the syncytiotrophoblast of placental villi from placenta accreta than those from normal placental tissues in both the second and third trimesters (p ⫽0.005 and 0.012, respectively). Consensus also exists that Tie receptors and their ligands (angiopoietins) are responsible for a number of nonendothelial and endothelial effects in both physiologic and pathologic processes during placental development [30,43,46–48]. The presence of functional Tie-2 receptors in trophoblasts demonstrates a specific role for angiopoietins as regulators of trophoblast behavior in placental development [51]. The interactions between Tie-2 and its ligands (Ang-1 and Ang-2) are involved in the well-prepared endometrium, trophoblast invasion, and remodeling of the maternal vasculature during the peri-implantation stage [52]. With longer exposure or at higher concentrations, Ang-2 acts as a Tie-2 agonist (or a partial agonist) in cultured endothelial cells [46,53]. Despite Ang-1-induced Tie-2 phosphorylation being essential to initiate angiogenesis, several studies have demonstrated that Ang-2 and VEGF alone can promote a rapid increase in capillary diameter, remodeling of the basal lamina, and new vessel growth, evidenced by sprouting of existing blood vessels [54–56]. Thus, the increased placental Ang-2 level in our study, with the concomitantly upregulated VEGF expression found previously [33], would result in an overall destabilization

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of uterine vasculature and enhance the neovascularized phenomenon found in placenta accreta. In a variety of invasive, highly vascular malignancies [57–60], Ang-2 exhibits overexpression and is responsible for tumorigenesis, vasculature remodeling, and tumor progression. Although Tie-2 is overexpressed in colorectal carcinoma, it is not remarkably expressed in pancreatic carcinoma. Therefore, the decreased Tie-2 expression in syncytiotrophoblasts found in our study might imply a negative feedback response rather than a primary event during the formation of the profuse vascular networks responsible for massive peripartum hemorrhage.

We found that MMP family molecules were not significantly upregulated in placenta accreta. Therefore, the association of these invasion-related molecules with placenta accreta is unlikely. We have found that upregulated EGFR, VEGF and Ang-2 are related to the development of placenta accreta [16,33,50]. Although the induction of MT1-MMP has the ability to upregulate EGFR, VEGF and Ang-2 [78–81], the decreased expression of MT-MMPs in placenta accreta shown in our study may represent in situ downregulation or negative feedback by other microenvironmental factors.

Conclusion Matrix Metalloproteinase and TIMP The extracellular matrix proteolytic machinery is known to play a major role in trophoblast invasion, a process that shares similar features with the pathology of tumor invasion [61]. Trophoblast invasion involves the degradation of extracellular matrix components by different kinds of enzymes [62]. The zinc-requiring matrix metalloproteinase (MMP) family is considered to be primarily responsible for matrix degradation and plays an important role in angiogenesis [63,64]. Four main groups, including collagenases, gelatinases, stromelysins, and membrane-type (MT) MMPs, have been categorized with at least 20 members [65,66]. MMP-2 and MMP-9 (type IV collagenases) are particularly important for the penetrative ability of cytotrophoblasts in vitro and in vivo [13,63,67,68]. MT1-MMP and MT2-MMP have also been shown to play a crucial role in trophoblast invasion [9,69,70]. Both are potential membrane-associated physiologic activators of MMP-2 and are expressed by proliferating and invasive trophoblasts during pregnancy [69–72]. Furthermore, the expression of MMPs is regulated by TIMP. TIMP-1 (an inhibitor of all known MMPs) and TIMP-2 (a preferential inhibitor of MMP-2) [73,74] are expressed by decidual cells and, to a certain degree, by extravillous trophoblasts [62,75–77]. We have shown that immunoreactive bands on Western blot analyses indicate that expression of both 66- and 60-kDa forms of MT1-MMP in second-trimester placentas and the 68-kDa form of MT2-MMP in thirdtrimester placentas are significantly decreased in tissues from placenta accreta (p ⫽0.025, 0.006, and 0.043, respectively; unpublished data). All other protein factors studied (MMP-2, MMP-9, TIMP-1, TIMP-2) were not significantly different in complicated and uncomplicated pregnancies (p > 0.05). RT-PCR for these factors did not demonstrate significant differences between the two groups (p > 0.05).


The pathogenetic mechanisms of placenta accreta are complicated and multifactorial. Although our data are not supported by animal disease models, we believe that growth-, angiogenesis- and invasion-related factors may play an additive or synergistic role in the pathogenesis of placenta accreta. In addition, we acknowledge that decidual defect is still a major contributing factor in the formation of placenta accreta. The impact of stromal and/or myometrial factors, which allow trophoblasts to invade deep into the myometrium, needs to be clarified. Further studies are needed in order to understand the responsible signaling molecules and possible genetic events, with intrauterine medical therapy as the ultimate goal.

Acknowledgments This study was supported by grants from Taichung Veterans General Hospital (TCVGH-926406C, -936405C and -946404C) and the National Science Council (NSC 94-2314-B-075A-014), Taiwan.

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