The Role of BMP and TGFβ in Failed Trophoblast Invasion and Preeclampsia

Abstract

Mainly defined by high blood pressure and proteinuria, the pregnancy disorder preeclampsia (PE) affects 2-8% of all pregnancies and is a leading cause of maternal and fetal mortality worldwide. Abnormal placentation in early pregnancy is thought to be the main reason for the development of the disorder which reconciles with the fact that delivery of the placenta is the only known cure. During normal placental development fetal cytotrophoblasts (CTBs) acquire an invasive phenotype where they undergo epithelial-to-mesenchymal transition (EMT) and invade the maternal spiral arteries. When the invading trophoblasts (TBs) are ready to settle down within the arteries, they undergo mesenchymal-to-endothelial transition (MEndT) where they upregulate vascular markers. This process, often termed pseudovasculogenesis, results in dramatic remodeling where high-resistance arteries become low-resistance vessels which can provide sufficient blood flow through the placenta to sustain fetal growth. In PE the CTBs fail to acquire this invasive property, by yet an unknown molecular mechanism, resulting in an inadequate blood flow through the placenta. Our data shows that the secreted angiogenic molecule epidermal growth factor-like protein 7 (EGFL7) is a downstream target of BMP9/ALK1 signaling and promotes endothelial sprouting. Studies have shown EGFL7 to promote invasion of endothelial cells (ECs), and its expression has been detected in TBs. Reports on gene expression analysis of placentae from PE woman revealed reduced expression of members of the BMP signaling pathway such as EGFL7 and ALK1. The soluble form of Endoglin, a co-receptor of BMP9, has shown to be upregulated in PE. Even though its pathogenic role in PE is still unclear, its soluble form has been suggested to act as a ligand trap for BMP9. Thus, the aim of this project was twofold. First, to investigate the effect of the BMP9/ALK1 pathway on TB invasion and pseudovasculogenesis and second, to analyze the molecular pattern of these factors in both placentae and serum of women suffering from PE compared to healthy controls. Results showed that overexpression of ALK1 in TBs did not induce pseudovascularization. Results demonstrated that TGFβ might have a regulatory role in TB invasion. Our results also suggest a non-pathogenic role for sENG in PE as it seems to bind BMP9 in both healthy and PE serum. However, ENG expression was shown to be lower in healthy placenta compared to PE, supporting the sENG ligand trap hypothesis. EGFL7 was strongly expressed in both healthy and PE placentae, while BMP9 expression was more prominent in healthy placenta compared to PE.Shedding light on the role of TGFβ family members in failed TB invasion and pseudovasculogenesis, will hopefully contribute to development of targeted molecular therapies to minimize the risk of PE and lead to better prognosis.