Gene expression changes and a decreased sensitivity for KCl in aortic tissue during experimental preeclampsia in rats
Authors: Lip Simone V. , Plösch Torsten , Boekschoten Mark V. , Faas Marijke M. 
Published: November 2023

Introduction

Adaptations of the maternal vasculature during pregnancy are required to ensure healthy development of the placenta and fetus. During preeclampsia these adaptations are not well established, resulting in the main characteristics of preeclampsia; maternal hypertension and proteinuria. The effects of preeclampsia on the maternal cardiovascular system is not yet fully understood.

Objectives

Compare vascular gene expression pattern and contractility of aortic tissue during experimental preeclampsia in the rat with healthy pregnant rats.

Methods

We used our previously established model for preeclampsia. Pregnant Wistar outbred rats were infused with low‐dose lipopolysaccharide at day 14 of pregnancy to induce experimental preeclampsia (ExpPE) (n=5). Control pregnant rats were infused with saline (n=5) at the same gestational day. At day 20 of pregnancy, the animals were terminated and aortas were isolated. Total abdominal aortic RNA was isolated and gene expression was measured by GeneChip Rat Gene 1.1 ST arrays (Affymetrix, Santa Clara CA). Gene Set Enrichment Analysis (GSEA) was performed to compare the two groups. Thoracic aortic rings (2 mm) were equilibrated for 30 minutes. Thereafter, the aortic rings were stimulated with KCl (60 mM) and the maximum contraction was measured.

Results

526 Genes were significantly (p‐value < 0.05, fold‐change > 1.4 or < −1.4) altered in ExpPE compared to healthy pregnant controls. GSEA showed highly significant (p‐value < 0.001 and a False Discovery Rate q‐value < 0.001) positive enrichment in ExpPE, compared to healthy pregnant animals, in “potassium channels” (Normalized Enrichment Score (NES) = 2.40, mostly contributing genes: Kcna6, Kcnh8 and Hcn4), “neuronal system” (NES = 2.40, mostly contributing genes: Kcna6, Cacng3, Syn3) and “striated muscle contraction” (NES = 2.35, mostly contributing genes: Myh8, Tnni1, Myh3) gene sets. The contractility assay of the aortic rings with KCl stimulation showed that the maximum contraction of ExpPE aortic rings was significantly (p‐value < 0.05) decreased compared to the healthy pregnant control animals.

Discussion

Potassium channels are known to play an important role in the establishment of the membrane potential, influencing the depolarization/repolarization of cells which affects the contractility of vascular smooth muscle cells. Vascular smooth muscle cells are also under the control of the autonomic nervous system. Changes in neuronal innervation of the aorta suggest an altered vasodilation/constriction response after neuronal stimuli.

Conclusions

Our data showed that experimental preeclampsia in rats resulted in changes in gene expression levels in the aorta and a decreased sensitivity to KCl of aortic rings compared to healthy pregnant rats. The data suggest that potassium channels and neuronal innervation in the aorta may play a role in the pathophysiology of experimental preeclampsia. If these changes are also present in preeclamptic women needs to be further investigated.

Support or Funding Information

We acknowledge the support from the Dutch Heart Foundation 2013T084