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bioRxiv · 10.1101/2020.08.21.261420

Insulin-like growth factor 1 signaling in the placenta requires endothelial nitric oxide synthase to support trophoblast function and normal fetal growth

Wilson, R. L.·Troja, W.·Sumser, E. K.·Maupin, A.·Lampe, K.·Jones, H. N.
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Abstract

Currently, there is no effective treatment for placenta dysfunction in utero. In a ligated mouse model of fetal growth restriction (FGR), nanoparticle-mediated human insulin-like 1 growth factor (hIGF1) gene delivery (NP-Plac1-hIGF1) increased hIGF1 expression and maintained fetal growth. However, whether it can restore fetal growth remains to be determined. Using the endothelial nitric oxide synthase knockout (eNOS-/-) mouse model, a genetic model of FGR, we found that despite inducing expression of hIGF1 in the placentas treated with NP-Plac1-hIGF1 (P=0.0425), FGR did not resolve. This was associated with no change to the number of fetal capillaries in the placenta labyrinth; an outcome increased with NP-Plac1-hIGF1 treatment in the ligated mouse model, despite increased expression of angiopoietin 1 (P=0.05) and suggested IGF1 signaling in the placenta requires eNOS to modulate placenta angiogenesis. To further assess this hypothesis, we used the BeWo Choriocarcinoma cell line and human placenta explant cultures that were treated with NP-Plac1-hIGF1, oxidative stress was induced with hydrogen peroxide (H2O2) and NOS activity inhibited using the inhibitor L-NMMA. In both BeWo and explants, the protective effect of NP-Plac1-hIGF1 treatment against H2O2 induced cell death/lactate dehydrogenase release was prevented by eNOS inhibition (P=0.003 and P<0.0001, respectively). This was associated with an increase in mRNA expression of oxidative stress markers HIF1 (P<0.0001) and ADAM10 (P=0.0002) in the NP-Plac1-hIGF1+H2O2+L-NMMA treated BeWo cells. These findings show for the first time the requirement of eNOS/NOS in IGF1 signaling in placenta cells that may have implications for placental angiogenesis and fetal growth.

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Wilson, R. L., Troja, W., Sumser, E. K., Maupin, A., Lampe, K., Jones, H. N.. 2020-08-23. Insulin-like growth factor 1 signaling in the placenta requires endothelial nitric oxide synthase to support trophoblast function and normal fetal growth. https://doi.org/10.1101/2020.08.21.261420

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