AUTHOR=Davenport Baylea N. , Jones Helen N. , Wilson Rebecca L. 

TITLE=Placental treatment with insulin-like growth factor 1 via nanoparticle differentially impacts vascular remodeling factors in guinea pig sub-placenta/decidua

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.1055234

DOI=10.3389/fphys.2022.1055234

ISSN=1664-042X

ABSTRACT=<p>Clinically, fetal growth restriction (FGR) is only detectable in later gestation, despite pathophysiological establishment likely earlier in pregnancy. Additionally, there are no effective <italic>in utero</italic> treatment options for FGR. We have developed a nanoparticle to deliver <italic>human insulin-like 1 growth factor</italic> (<italic>hIGF-1</italic>) in a trophoblast-specific manner which results in increased expression of <italic>hIGF-1</italic>. IGF-1 signaling in the placenta regulates multiple developmental processes including trophoblast invasion and maternal vascular remodeling, both of which can be diminished in the FGR placenta. We aimed to determine the effects of short-term <italic>hIGF-1</italic> nanoparticle treatment on sub-placenta/decidua trophoblast signaling mechanisms in FGR and under normal growth conditions. Using the guinea pig maternal nutrient restriction (MNR) model of FGR, ultrasound-guided, intra-placenta injections of <italic>hIGF-1</italic> nanoparticle were performed at gestational day 30–33, and dams sacrificed 5 days later. Sub-placenta/decidua tissue was separated from placenta for further analyses. Western blot was used to analyze protein expression of ERK/AKT/mTOR signaling proteins (phospho-Erk (pERK), phospho-Akt (pAKT), raptor, rictor and deptor). qPCR was used to analyze gene expression of vascular/remodeling factors [<italic>vascular endothelial growth factor</italic> (<italic>Vegf</italic>), <italic>placenta growth factor</italic> (<italic>Pgf</italic>), <italic>platelet-derived growth factor</italic> (<italic>Pdgf</italic>)) and tight junction/adhesion proteins (<italic>claudin 5</italic> (<italic>Cldn5</italic>), <italic>p-glycoprotein</italic> (<italic>Abcb1</italic>), <italic>occludin</italic> (<italic>Ocln</italic>) and <italic>tight junction protein 1</italic> (<italic>Zo1</italic>)]. MNR reduced expression of pERK, <italic>PdgfB</italic> and <italic>Cldn5</italic>, and increased expression of <italic>Ocln</italic> and <italic>Zo1</italic> in the sub-placenta/decidua. In MNR + <italic>hIGF1</italic> nanoparticle sub-placenta/decidua, expression of <italic>PdgfB</italic>, <italic>Ocln</italic> and <italic>Zo1</italic> was normalized, whilst pAkt, <italic>VegfB</italic>, <italic>Vegf receptor 1</italic> and <italic>PdgfB receptor</italic> were increased compared to MNR. In contrast, <italic>hIGF-1</italic> nanoparticle treatment of normal placentas reduced expression of pERK, raptor and increased expression of the mTOR inhibitor deptor. This was associated with reduced expression of <italic>VegfA</italic>, <italic>Plgf</italic>, and <italic>PdgfB</italic>. Here we have shown that the impact of <italic>hIGF-1</italic> nanoparticle treatment is dependent on pregnancy environment. Under MNR/FGR, <italic>hIGF-1</italic> nanoparticle treatment triggers increased expression of growth factors and normalization of EMT factors. However, under normal conditions, the response of the placenta is to decrease AKT/mTOR signaling and growth factor expression to achieve homeostasis.</p>