Long-term cardiovascular disorders in the STOX1 mouse model of preeclampsia

Francisco Miralles,Céline Méhats,Daniel Vaiman,Gilles Renault,Angéline Duché,Céline Bertholle,Isabelle Lagoutte,Hélène Collinot,Yasmine Boumerdassi,Sébastien Jacques,Carmen Marchiol,Muriel Andrieu,Aurélien Ducat

doi:10.1038/s41598-019-48427-3

Francisco Miralles, Céline Méhats + Show 11 more

Open Access

https://doi.org/10.1038/s41598-019-48427-3

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Abstract

Adverse long-term cardiovascular (CV) consequences of PE are well established in women. However, the mechanism responsible for that risk remains unknown. Here, we mated wild-type female mice of the FVB/N strain to STOX1A-overexpressing mice to mimic severe PE and investigated the long-term consequences on the maternal cardiovascular system. Ultrasonography parameters were analyzed in mice before pregnancy and at 3 and 6 months post-pregnancy. At 6 months post-pregnancy, cardiac stress test induced by dobutamine injection revealed an abnormal ultrasonography Doppler profile in mice with previous PE. Eight months post-pregnancy, the heart, endothelial cells (ECs) and plasma of females were analyzed and compared to controls. The heart of mice with PE showed left-ventricular hypertrophy associated with altered histology (fibrosis). Transcriptomic analysis revealed the deregulation of 1149 genes in purified ECs and of 165 genes in the hearts, many being involved in heart hypertrophy. In ECs, the upregulated genes were associated with inflammation and cellular stress. Systems biology analysis identified interleukin 6 (IL-6) as a hub gene connecting these pathways. Plasma profiling of 33 cytokines showed that, 8 of them (Cxcl13, Cxcl16, Cxcl11, IL-16, IL-10, IL-2, IL-4 and Ccl1) allowed to discriminate mice with previous PE from controls. Thus, PE triggers female long-term CV consequences on the STOX1 mouse model.

Highlights

Preeclampsia (PE), a major hypertensive disease of pregnancy, is an important risk factor for cardiovascular disease (CVD) in women[1]
Epidemiological studies suggest that PE represents a risk factor for CVD in the long-term after pregnancy[10]
In this study, using the STOX1 model of PE, we demonstrate that PE can produce long-term effects on the health of the maternal cardiovascular system (CVS) by itself

Summary

Introduction

Preeclampsia (PE), a major hypertensive disease of pregnancy, is an important risk factor for cardiovascular disease (CVD) in women[1]. In PE, defective vascularization of the placenta causes the production and release of anti-angiogenic factors These factors affect the maternal cardiovascular system (CVS) triggering a systemic endothelial activation responsible for hypertension and kidney dysfunction[3]. The long-term risk of cardiovascular and cerebrovascular disease is doubled in women with PE, as compared with women of the same age This risk is even higher for women with recurrent preeclamptic pregnancies[8]. The long-term increase in CVD in women with PE may result from shared risk factors, subtle vascular damage, or persistent www.nature.com/scientificreports/. Www.nature.com/scientificreports endothelial dysfunction caused by the disease and playing a synergistic harmful role with the aging of the vascular system. None of these (not mutually exclusive) assumptions is currently favored. Several studies have used animal models of PE to evaluate the long-term consequences on the mother at various times post-pregnancy and on specific outcomes, such as blood pressure, vascular reactivity, proteome, abnormal heart structure, vascular reactivity, aortic function, brain inflammation[12,13,14,15]

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