PROJECT SUMMARY / ABSTRACT
Preeclampsia (PE) is a hypertensive disorder and one of the leading causes of fetal/maternal
morbidity and mortality during pregnancy. PE is characterized by impaired fetal and maternal endothelial
function and excessive inflammation. Children born to PE will face increased risks of cardiovascular
disorders later in life, suggesting that PE programs fetal vascular cells in utero. To date, the mechanisms
underlying PE-associated fetal endothelial dysfunction remain elusive. Maternal obesity is one of the
prevalent risk factors that associated with PE in developed countries. Maternal obesity increases the
overall risk of PE by 3 fold. Children born to obese mother also exhibit higher blood pressure and
increased risks of adverse cardiovascular outcomes in adulthood. Elevated TNFa and TGFß1 levels are
associated with endothelial dysfunction in PE. Compared with lean subjects, obese women have
increased pro-inflammatory cytokines (e.g. TNFa) levels in placenta and increased TGFß1 levels in
maternal circulation. Human umbilical vein is the blood vessel transporting all nutrition, O2, and other
humoral factors (e.g. cytokines) from the placenta and maternal system into the fetus. Hence, human
umbilical vein endothelial cells (HUVECs) is widely used as a human fetal endothelial cell model. MiR192-
5p is a cardiovascular diseases-associated microRNA which regulates endothelial cell growth in cultured
HUVECs. Our preliminary data have shown that increased miR192-5p expression inhibits the TNFa- and
TGFß1-induced cell migration in HUVECs. We and others have reported that PE decreases miR192
expression in freshly isolated and unpassaged (P0)-HUVECs and in placentas. Our data further
demonstrated that i) PE downregulated miR192-5p in male but not in female P0-HUVECs from lean
pregnancies; ii) PE upregulated miR192-5p in both female and male P0-HUVECs from obese
pregnancies; and iii) Male P1-HUVECs from lean PE exhibit weaker responses (monolayer integrity) to
TNFa and TGF-ß1 than female cells did. As TNFa and TGFß1 are both upstream regulators of miR192-
5p, these data suggest that miR192-5p plays an important and differential role in TNFa and/or TGFß1-
regulated fetal endothelial function in lean and obese PE. Overall hypothesis: PE programs fetal
endothelial cells by dysregulating endothelial function-associated microRNAs and their target genes,
leading to fetal endothelial dysfunction, and ultimately laying the groundwork for adult onset
cardiovascular disorders in children born to PE. Specifically, in this application, I will test the hypothesis
that miR192-5p differentially regulates the PE-induced fetal endothelial dysfunction in lean and obese
pregnancies via the TNFa and/or TGFß1 signaling pathways using HUVECs as a model. Results from
our proposed studies will advance our understanding of the roles of miRNAs in PE-induced fetal sex-
specific endothelial dysfunction in lean and obese pregnancies. In the long term, these studies may reveal
novel biomarkers or therapeutic targets for fetal sex-specific cardiovascular risk prediction, treatment,
and even prevention in children born to lean and obese PE.
