Preeclampsia affects 3–5% of pregnancies and is the worldwide leading cause of maternal and perinatal death (Fox et al., 2019). It is characterized by high blood pressure and organ dysfunction (brain, kidneys, liver, and uterus) in pregnancy (Fox et al., 2019). The causes of preeclampsia remain unclear, but placental dysfunction is important (Huppertz, 2008). The only ‘cure’ is delivery of the placenta; this is unsatisfactory because clinicians must choose optimal delivery time balancing risks from preeclampsia vs. the risks from fetal prematurity.

Transthyretin (TTR) is a homo-tetrameric binding protein that is synthesized and secreted by hepatocytes (Blaner et al., 1991; Dickson et al., 1982), placenta (McKinnon et al., 2005) and choroid plexus (Chanoine et al., 1992) and taken up by hepatocytes (Landers et al., 2019), kidney (Sousa et al., 2000) and trophoblasts (Landers and Richard, 2017; Landers et al., 2009). Its main function is thought to be binding and transport of thyroid hormones in serum however TTR also binds many other endo- and xenobiotics and may serve a role in clearing these compounds from the circulation (Buxbaum and Reixach, 2009). TTR is often identified in proteomics studies of preeclampsia, but whether it is causative or protective is unknown (Navajas et al., 2021; Zhu et al., 2014).

Endoglin is a type 1 membrane glycoprotein that forms part of the receptor complex for transforming growth factor beta 1 (TGF-β1) (Cheifetz et al., 1992). In preeclampsia (and in some cancers), matrix metalloproteases cleave the extracellular part of endoglin to produce soluble endoglin (sEng) which is released into the bloodstream where it causes vascular dysfunction (Hawinkels et al., 2010, Kaitu'u-Lino et al., 2013). Its effects in serum are thought to be through binding to and therefore blocking the normal actions of TGF-β1, which is required for normal angiogenesis (Rana et al., 2019). When compared to pregnant women without a hypertensive disorder, sEng levels are approximately six times higher in the serum of women with preeclampsia (Rana et al., 2012) and this contributes to the hypertension and placental perfusion problems that are typically associated with preeclampsia.

In a rodent model of preeclampsia, administration of wild type TTR reduced vascular problems and the authors proposed this may be due to binding to sEng (Kalkunte et al., 2013). In this study, we aimed to confirm if TTR binds sEng, address how TTR may bind to sEng, whether it competes with TGF-β1 for sEng binding and whether hepatocytes can clear TTR-sEng from the cell culture medium. If TTR plays a role in the clearance of sEng from the circulation, this study could provide a rationale for therapies that increase TTR levels to treat those at highest risk of developing preeclampsia.