In:
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 320, No. 5 ( 2021-05-01), p. R653-R662
Abstract:
Currently, there is no effective treatment for placental 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 placental labyrinth; an outcome which was 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, BeWo choriocarcinoma cell line and human placental explant cultures were treated with NP-Plac1-hIGF1, oxidative stress was induced with hydrogen peroxide (H 2 O 2 ), and NOS activity was inhibited using the inhibitor N G -monomethyl-l-arginine (l-NMMA). In both BeWo cells and explants, the protective effect of NP-Plac1-hIGF1 treatment against H 2 O 2 -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 hypoxia inducing factor 1α ( HIF1α; P 〈 0.0001) and ADAM10 ( P = 0.0002) in the NP-Plac1-hIGF1 + H 2 O 2 + 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.
Type of Medium:
Online Resource
ISSN:
0363-6119
,
1522-1490
DOI:
10.1152/ajpregu.00250.2020
Language:
English
Publisher:
American Physiological Society
Publication Date:
2021
detail.hit.zdb_id:
603839-6
detail.hit.zdb_id:
1477297-8
SSG:
12
