Preeclampsia: new insights into the mechanisms of sFlt-1 and soluble Endoglin release (#146)
Preeclampsia is one of the most serious complications of pregnancy. In the past decade, a significant advance has been made in the field with the discovery of soluble Flt-1 (sFlt-1; splice variant(s) of the VEGFR1 receptor) and soluble endoglin (sEng) as the likely ‘toxins’ of preeclampsia. They are released from the hypoxic preeclamptic placenta and spread throughout the maternal circulation, causing endothelial dysfunction and end-organ injury.
The importance of identifying sEng and sFlt-1 is that they represent potential drugs targets. Conceivably, neutralising their release or biological activity may be a strategy to quench disease severity. Unfortunately, the mechanism of their release has not been described. Our laboratory has therefore sought to describe the final molecular events that leads to the release of these anti-angiogenic factors.
We recently reported the mechanism of sEng release1. Membrane bound MMP-14 on the surface of preeclamptic placentas cleaves Endoglin, releasing sEng into the maternal circulation1. We are currently raising antibodies to identify approaches to jam this interaction as a potential therapeutic strategy.
We have also interrogated other membrane MMP’s for their potential roles in sEng release. While MMP15 is upregulated in preeclampsia, it has no effect on sEng release2. Interestingly, MMP17 may suppress sEng release, possibly by inhibiting MMP14 activity.
Given the numerous reports describing the association between sFlt1 and preeclampsia, it is perhaps surprising the molecular mechanism that results in elevated sFlt-1 production has not been reported. Recently, jumonji domain containing protein 6 (Jmjd6) was shown to be an oxygen-sensing molecule that promotes vascular haemostasis3. With low oxygen, Jmjd6 directly interacts with U2AF65, the spliceosome component that appears directly involved in the regulation of Flt-1 splicing to produce sFlt-1. We have generated data suggesting Jmjd6 may indeed be a key molecule within placenta that senses low oxygen and mediates an increase in sFlt-1 production by interacting with U2AF65. This may be the molecular mechanism regulating sFlt-1 production in preeclampsia.
1. T. Kaitu’u-Lino, Palmer et al Am J Path 2012
2. T. Kaitu’u-Lino et al PLOS One 2012
3 Boeckel JN, et al. Proc Natl Acad Sci 2011