Role of Placenta FGL2 in the Development of Preeclampsia
Consensus has been reached amongst many physicians and researchers that preeclampsia (PE) is not a single disease with common pathophysiology, instead the clinical manifestations of PE are likely a common end-point for different maternal and placental pathologies. Using molecular tools shown to be effective in tackling this same quagmire in other fields of medicine (i.e., oncology), we have successfully identified three subclasses of PE disease with different underlying pathophysiology. Our results have demonstrated that PE is the result of: 1) maternal maladaptation to pregnancy; 2) insufficient utero-placental blood flow; or, 3) excessive immune activation at the maternal-fetal interface (PMID: 25679511, 27160201). Most recently we have turned our attention to better understanding of the ‘immune-driven’ subclass of PE, as this group of women are often overlooked in the traditional descriptions of PE pathophysiology. In this smaller subclass of PE patients, accounting for ~ 10% of the PE population, we have demonstrated excessive placental gene expression of Fibrinogen-Like Factor 2 (FGL2). This placental protein may act as a both a marker of a proinflammatory state at the maternal-fetal interface and a mediator of immune imbalance and thrombosis in these women.
The known functions of FGL2 include immune modulation and fibrin deposition, both well characterized components of the PE phenotype. Further, the membrane bound FGL2 protein can be cleaved to yield a secreted form, possibly identifying FGL2 as a promising biomarker candidate specifically for this immune-driven subclass of PE patients. Ongoing research in the lab is currently characterizing lesions within the human placenta that are specifically associated with heightened FGL2 expression within the immune-driven subclass of PE. Further work is ongoing to develop a mouse model of placenta-specific FGL2 overexpression to evaluate its causal role in the development of placental dysfunction and maternal signs of PE in late gestation.