The LINC00200/SERPINE-1 axis is a potential molecular framework underlying ROP protection in preeclampsia

Abstract

Purpose : Retinopathy of prematurity (ROP) is an interruption of retinal vascular maturation in preterm infants which we cannot cure or prevent. Preeclampsia is associated with decreased ROP risk in both humans and animals. While this suggests placental contribution to ROP risk, the underlying molecular mechanisms are not clear. We have identified the long non-coding RNA species, LINC00200, as a possible mediator underlying protection. Herein, we examine gene expression and DNA methylation within placental and peripheral tissue from preterm gestations with disparate ROP risk and gestational preeclampsia.

Methods : Placental tissue, peripheral blood and clinical data were collected for a discovery cohort of preterm infants with (n=14) or without (n=16) ROP. Infinium MethylationEPICBeadChip was performed on placental tissue or peripheral white blood cells (WBC) and differentially methylated regions identified relative to preeclampsia or ROP. Multi-pronged expression analysis included whole transcriptome analysis within the discovery cohort and focused LINC00200 activation target SERPINE-1 analysis within a replication cohort consisting of placental (ROP n=8; control n=6) or WBC (ROP n=6; control n=6) RNA or plasma protein using qRT-PCR and ELISA, respectively. Statistical associations were assessed using a paired t-test.

Results : We found significant LINC00200 hypermethylation within ROP-associated placental tissue, supporting whole transcriptome placental data showing decreased LINC00200 expression relative to ROP. Downstream analysis demonstrated significantly decreased SERPINE-1 placental expression (p<0.01) in infants with ROP by RT-PCR, as well as within postnatal circulation at gestational age 31-33 weeks (p<0.05) for preterm infants who developed ROP by ELISA. Conversely, SERPINE-1 expression was increased within infant plasma for preeclamptic gestations (p<0.05).

Conclusions : We identify a significant association between LINC00200 hypermethylation and decreased LINC00200 expression within ROP-associated placental tissues. Further, we find a significant association between decreased SERPINE-1 expression and ROP, though an inverse association for preeclamptic gestations. This identifies the LINC00200/SERPINE-1 axis as a potential molecular framework underlying ROP protection in preeclampsia which is established in-utero and maintained in the postnatal circulation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.