Q&A Report: Preeclampsia: From Hippocrates to Contemporary Research
Would it be possible to explore the use of TLR9 antagonists as a treatment option in preeclampsia animal models?
This review paper describes the potential use of TLR inhibitors in preterm birth and fetal inflammatory injury: PMID 32313651, while this paper discusses the potential use of hydroxychloroquine (non-specific inhibitor of TLR9) in preeclampsia: PMID 3163382.
For stimulation of TLR9 contractile response during pregnancy, was this prevented by hydralazine treatment? Does this stage of pregnancy correlate to 3rd trimester or full term?
We have not used hydralazine treatment in our studies. There are a few differences between rodent and human pregnancy. In most of our studies, we start exposure to synthetic TLR9 agonists or mtDNA on GD14, which corresponds mostly to the second trimester of human pregnancy. In rats and mice, fetal organs, such as the brain, continue developing postnatally.
Any relationship between cf-mtDNA and severity of proteinuria in preeclamptic animals?
Proteinuria is not a reliable finding in animal models with preeclampsia-like signs and we don’t measure it usually.
Any cardiac function assessment during TLR9 agonist administration in the animals?
We have not assessed cardiac function in these animals but it is something we are very interested in.
Do you think this can be a new mouse model for preeclampsia and do we have any knowledge as to how eclampsia develops? For example seizure, coma hemorrhage?
I think using TLR9 agonists or other inflammatory agents to induce preeclampsia-like signs is a good approach in rodent and murine models if your interest is in the inflammatory/immune mechanisms underlying preeclampsia. This paper has made comparisons between the outcomes of various inflammatory triggers: PMCID: PMC10569118 – We do not know exactly how a patient transitions from preeclampsia to eclampsia.
Along the same line and considering the limitations animal models may have, what would you suggest is an appropriate model of preeclampsia in mice?
It all depends on what features of preeclampsia you are interested in. At present, no single model recapitulates the full phenotype of preeclampsia and most importantly, there is no model to mimic the various clinical subtypes of preeclampsia.
Is the reduction in cf-mtDNA in preeclampsia a manifestation of a general reduction in mitochondrial function? Does it reflect a general reduction in mitochondrial numbers?
I don’t have the answer right now but we are working on this.
I'd like to know if you have looked into macrophages production of mtDNA too?
We have not looked at release of mtDNA from macrophages. Others though have (see PMCID: PMC9197407) but this work is not in preeclampsia.
Does PCOS endothelia dysfunction involve hypoxia-induced NFkappaB inflammatory cytokines?
There is evidence to connect endothelial dysfunction, inflammation, and PCOS. The exact mechanisms governing this relationship are not well understood. I am not an expert in PCOS, however, and an expert in this field may have a more detailed answer to your question.
Has genetic disposition been explored as a possible risk factor for the development and severity of preeclampsia?
Heritability of preeclampsia has been estimated to be 45-60% but the exact mechanisms are not well understood or explored. My lab is working with Dr. Nicole Phillips from the University of North Texas Health Science Center in studies that aim to understand the contribution of mitochondrial genetics to preeclampsia.