Fetal growth restriction occurs in 10% of pregnancies and is the most common risk factor for stillbirth. Retinitis Pigmentosa GTPase Regulator Interacting protein 1 like (RPGRIP1L) is essential for placental vascular development, with a mouse knockout model displaying impaired placental development (1). We explore RPGRIP1L in human placenta from FGR pregnancies and perform functional studies examining its role in placenta subjected to FGR stress conditions; hypoxia and low glucose.
RPGRIP1L was significantly increased (p<0.005, n=11, n=17 control) in placenta from term FGR pregnancies. Hypoxia (1% Oxygen) increased RPGRIP1L in term trophoblasts (p<0.0025) and decreased RPGRIP1L in isolated first trimester cytotrophoblasts (p=0.0079). No changes were observed with low glucose. Immunohistochemistry demonstrated expression of RPGRIP1L within extravillous trophoblasts, synctiotrophoblast and in the endothelium.
RPGRIP1L is known to be involved in the Sonic Hedgehog pathway which governs placental differentiation, proliferation, migration and invasion. We explored the expression of Smoothened (SMO), Suppressor of fused homolog (SUFU) and Sonic hedgehog (SHH) upstream of RPGRIP1L, and Glioma-associated oncogene (GLI); GLI1/2/3 genes downstream of RPGRIP1L. Hypoxia increased SMO in the first trimester (p=0.0079) and decreased SMO at term (p=0.008). SMO induces GLI target gene expression. Thus, as expected, we observed decreases and increases in GLI target gene expression in first trimester (GLI1; p=0.0079) and term cytotrophoblasts respectively.
RPGRP1L is upregulated in FGR placentas. Our in-vitro hypoxia experiments indicate RPGRIP1L is differentially regulated at different trophoblast gestations and is associated with changes within the sonic hedgehog pathway. This suggests that RPGRIP1L and the Sonic Hedgehog pathway may be involved in placenta development and insufficiency in first and term trophoblasts.