Fetal growth restriction (FGR) and
preeclampsia (PE) are often associated with abnormal maternal
inflammation, deficient spiral artery (SA) remodeling, and altered uteroplacental perfusion. Here, we provide evidence of a novel mechanistic link between abnormal maternal
inflammation and the development of FGR with features of PE. Using a model in which pregnant rats are administered low-dose
lipopolysaccharide (LPS) on gestational days 13.5-16.5, we show that abnormal
inflammation resulted in FGR mediated by
tumor necrosis factor-α (TNF).
Inflammation was also associated with deficient trophoblast invasion and SA remodeling, as well as with altered uteroplacental hemodynamics and placental nitrosative stress. Moreover,
inflammation increased maternal mean arterial pressure (MAP) and was associated with renal structural alterations and
proteinuria characteristic of PE. Finally,
transdermal administration of the
nitric oxide (NO) mimetic
glyceryl trinitrate prevented altered uteroplacental perfusion, LPS-induced
inflammation, placental nitrosative stress, renal structural and functional alterations, increase in MAP, and FGR. These findings demonstrate that maternal
inflammation can lead to severe
pregnancy complications via a mechanism that involves increased maternal levels of TNF. Our study provides a rationale for the use of
antiinflammatory agents or NO-mimetics in the treatment and/or prevention of
inflammation-associated
pregnancy complications.