HYPERTENSION DURING EARLY PREGNANCY IMPAIRS GENETIC PRIMING OF UTERINE ARTERIES PRIOR TO REMODELLING IN RODENTS

Abstract

Objective: During pregnancy the uterine spiral arteries undergo major vascular remodelling to ensure sufficient uteroplacental perfusion to support the fetus. In pregnancies complicated by hypertensive disorders this remodelling is deficient leading to impaired uteroplacental blood flow and poor maternal and fetal outcomes. Evidence suggests that the uterine arteries can be ‘primed’ by changes in gene expression and maternal factors to ensure appropriate remodelling takes place. This study aimed to examine the early-pregnancy associated gene expression changes in the uterine arteries (UAs) of stroke-prone spontaneously hypertensive rats (SHRSP) compared to their normotensive counterparts, Wistar-Kyoto rats (WKY). Design and method: SHRSP and WKY females were time-mated with males of the relevant strain. On gestational day (GD)6.5 dams were sacrificed, the UA collected and processed for RNA-sequencing alongside age-matched virgin controls (n = 3/group). Structure & function were assessed by wire and pressure myography. Gene expression changes were investigated using Ingenuity Pathway Analysis (IPA®) with padj > 0.05. Results: No structural or functional differences were observed in UAs between strains (SHRSP, WKY) or pregnancy (NP, P) using myography. SHRSP UAs showed a greater number of differentially expressed genes (DEGs) across pregnancy than WKY. WKY UAs exhibited an expression pattern of reduced Ca2+ handling and RAAS components with an increase in ATP production between NP and P states. SHRSP P UAs showed an increased expression of DEGs related to immune response, ROS production and downstream effectors of the RAAS in comparison to SHRSP NP UAs. These changes were not shared between strains. Conclusions: These results suggest SHRSP UAs experience gene expression changes in inflammation and oxidative stress pathways in early pregnancy that may induce failed priming of the UA. This may subsequently contribute to adverse vascular remodelling and placental ischaemia in later gestation characteristic of hypertensive pregnancies.