Preeclampsia and maternal dementia: exploration of cerebrovascular alterations and potential therapeutic targets
Preeclampsia (PE) is a specific pregnancy complication associated with hypertension and placental hypoperfusion, as well as a high concentration of circulating inflammatory factors secreted by the placenta, leading to an increased risk of adverse neonatal outcomes for both fetus and mother, along with consequences for neurovascular function. However, PE is not limited to pregnancy, and more than 20 years after this event, women remain at an increased risk of stroke and cognitive impairment. Clinical MRI studies have shown that these patients exhibit brain lesions. MAB2's work on a mouse model of PE has demonstrated the direct involvement of inflammatory factors, including prokineticins (PROKs) and their receptors. We have shown in a blood-brain barrier cellular model that PROKs modify vascular permeability.
Our recent results demonstrate a direct link between the preeclamptic event and the onset of late brain lesions and inflammation. Finally, recent metabolomics and proteomics results support the hypothesis of genome-wide histone modification profile disturbances that could be involved in vascular alterations and the development of vascular and/or neurodegenerative dementia.
The objective of the project is to characterize the vascular changes occurring at the time of PE and their long-term consequences on cognitive functions, and to determine potential therapeutic targets for preventive treatment. These objectives will be addressed through MRI studies, behavioral tests, and the analysis of epigenetic modifications using a mouse model of preeclampsia.
PREDEV project partners
Christel MARQUETTE ; BIOSANTE
Delphine PFLIEGER ; BGE EDYP
Sabine BRUGIERE ; BGE EDYP
Emmanuel BARBIER ; GIN IRMaGe
Mireille ALBRIEUX ; GIN
Lise MIGUEL, PREDEV project PhD student
Who is she?
I earned a bachelor's degree in Cell Biology and Physiology from the University of Limoges, where I discovered neuroscience. I then pursued a master's degree in Neuroscience at the University of Strasbourg.
During my first year of master's studies, I joined the Life Adversities and Pain team at the Laboratory of Cognitive and Adaptive Neurosciences in Strasbourg for an internship under the supervision of Professor Lelièvre and Edith Tanché. This project focused on the effects of gestational stress in Vasoactive Intestinal Peptide-deficient mouse embryos, aiming to study the placental, inflammatory, and behavioral consequences in adulthood. In my second year, I completed an internship at University College London, in the teams of Dr. Sandrine Géranton and Dr. Francesca Di Domenico. My work focused on the effects of radiotherapy and stress on pain perception in mice, studying the brain and spinal circuits involved in its modulation.
Currently, I am pursuing a PhD in neuroscience under the supervision of Christel Marquette at the Biosanté laboratory of CEA Grenoble. My project focuses on post-preeclampsia vascular dementias, and more specifically on the role of prokineticins in cerebrovascular alterations and the epigenetic modifications associated with preeclampsia.
Preeclampsia is a hypertensive pregnancy disorder characterized by placental hypoxia, inducing the release of several inflammatory and angiogenic factors, including prokineticins (PROK1 and PROK2). These proteins, by acting on their receptors (PROKR1 and PROKR2), impair the blood-brain barrier (BBB), leading to cerebrovascular lesions and inflammatory processes. Simultaneously, epigenetic modifications, particularly involving histones, may disrupt gene expression and contribute to neurodegenerative processes. In the long term, women who have suffered from preeclampsia present an increased risk of stroke and cognitive disorders.
My thesis aims to characterize, in a preeclamptic mouse model, cerebrovascular alterations using MRI, their long-term consequences on cognitive functions (Barnes maze test), as well as epigenetic modifications affecting the hippocampus, cortex, and BBB. Finally, the efficacy of a preventive treatment based on a prokineticin receptor antagonist will be evaluated to limit cerebrovascular damage and prevent cognitive deficits.
This project addresses a major public health challenge: improving the care of pregnant women and preventing cognitive complications that may arise several years after pregnancy.
Link to partner laboratories