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MitoVasc : physiopathologie cardiovasculaire et mitochondriale


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    Fetal programming of vascular function

    Fetal programming of vascular function

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    Céline Fassot

    Team members : 

    Céline Fassot, Ph.D., CRCN Inserm

    Jennifer Bourreau, Technician Inserm

    Cyrielle Payen, Ph.D. Student

    Abigaëlle Guillot, Ph.D. Student

    Charbel Mouawad, Ph.D. Student

     

     

    Cardiovascular disease is one of the greatest health burdens worldwide. Cardiovascular risk is not only determined by conventional risk factors in adult life, but also by early events resulting in re-setting of key physiological functions during fetal development. Indeed modifications of the in utero environment during specific windows of development are now recognized as important causes of fetal stress, leading to several responses such as loss of structure/function and pre-emptive adaptations to an adverse post-natal environment. This fetal programming leads to metabolic and vascular abnormalities resulting in cardiovascular diseases during adulthood.


     

    Maternal nutrition is one of the major intrauterine environmental factors that alters expression of the fetal genome and may have lifelong consequences leading to limited physiological functions and consequently to disease in offspring.

    Obesity or diabetes epidemics all around the world induce increased maternal obesity and diabetes during pregnancy. In addition, with the increase of women suffering from morbid obesity and the failure of medical therapies, bariatric surgery (BS) has rapidly emerged : sleeve gastrectomy (restrictive procedure) or gastric bypass (malabsorptive combined with restrictive procedure). If the maternal, obstetric and fetal complications of obese with or without BS or diabetic women during pregnancy are well demonstrated, little is known about long-term effects of maternal metabolic disorders in adult offspring, in particular in term of cardiovascular pathologies.

    Several animal models such as modification of maternal nutrition, reduction of uterine supply or glucocorticoids treatment have contributed to the understanding of some of the mechanisms involved in fetal/perinatal programming by showing that kidney changes and alterations of hormones regulation are involved in the fetal programming of metabolic and cardiovascular disorders.

    The aim of our group is to evaluate changes in vascular properties through physiological responses and epigenetic modifications in experimental models of fetal programming.

    We develop 3 different experimental models of fetal programming :

    1) A rat model of fetal exposure to maternal diabetes (streptozotocin-induced diabetes) characterized by moderate levels of maternal hyperglycemia, normal gestation and delivery with healthy pups without intrauterine growth retardation. Our first studies demonstrated that offspring from diabetic mother showed a specific gene expression profile in favour of vasoconstriction associated with the development of hypertension around 6 months of age.

     


    The unbalance between vasoactive agents in rats exposed in utero to maternal diabetes is associated with an important decrease of the prostacyclin receptor (IP receptor), inducing a decreased prostacyclin-induced vasodilatation from a pre-hypertensive stage (3 months of age). Recently, we also demonstrated the establishment of an abnormal vascular architecture in offspring exposed in utero to maternal diabetes.

    Now, we are interested in transgenerational impacts of maternal diabetes.

    2) A rat model of in utero exposure to maternal obesity induced by high fat diet. First of all, we evaluated vascular reactivity before the onset of metabolic disorders in offspring to highlight a fetal programming of vascular function independently of metabolic programming. Moreover, we evaluate the impact of post-natal diet modifications on metabolic and vascular functions on animals adopted by obese or control mothers.

    3) More recently, we developed rat models of sleeve gastrectomy and gastric bypass in order to evaluate the impact of bariatric surgery on offspring.

     

    Thus, our objectives are :

    - To determine the epigenetic profile of offspring exposed in utero to maternal metabolic disorders

    - To evaluate transgenerational impacts on F2 generation

    - To study mechanisms implicated in vascular remodeling at physiological and epigenetic levels.

    - To evaluate impact of maternal BS on vascular fetal programming

    - To determine the role of GPCR on endothelial cells response to disruption associated with metabolic disorders.

     

    Publications:

    • DibA, PayenC, BourreauJ, MunierM, GrimaudL, Fajloun  Z, LoufraniL, HenrionD,Fassot C. In utero exposure to maternal diabetes is associated with early abnormal vascular structure in offspring. Frontiers in Physiology, 2018; 9:350.
    • Begorre M.A., Dib A., Habchi K., Guihot A.L., BourreauJ., VessieresE.,  Blondeau B., Loufrani L., Chabbert M., HenrionD., Fassot C. Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. Scientific Reports, 2017 ; 7:45625.
    • VessieresE., DibA., BourreauJ., Lelièvre E., Custaud M.A., Lelievre-PegorierM., Loufrani L., HenrionD., Fassot C. Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed in Utero to Maternal Hyperglycaemia. PLoS One, 2016 ; 11:e0146830
    • Habbout A, Guenancia C, Lorin J, Rigal E, Fassot C, Rochette L, Vergely C. Postnatal overfeeding causes early shifts in gene expression in the heart and long-term alterations in cardiometabolic and oxidative parameters. PLoS One, 2013 ; 8:e56981
    • Freidja ML, Tarhouni K, Toutain B, Fassot C, Loufrani L, Henrion D. The AGE-Breaker ALT-711 Restores High Blood Flow-Dependent Remodeling in Mesenteric Resistance Arteries in a Rat Model of Type 2 Diabetes. Diabetes, 2012 ; 61:1562-1572.
    • Blondeau B., Joly B., Perret C., Prince S., Bruneval P., Lelièvre-Pégorier M., Fassot C., Duong Van Huyen J.P. In utero exposure to maternal diabetes leads to glucose intolerance and high blood pressure without major effect on lipid metabolism. Diabetes and Metabolism, 2011 ; 37 : 245-251.
    • Duong Van Huyen J.P., Troise A., Perret C., Prince S., Barbry P., Henrion D., Bruneval P., Laurent S., Lelièvre-Pégorier M., Fassot C. Abnormal vascular programming of prostacyclin receptor involved in hypertension in rats exposed in utero to maternal diabetes. Diabetes, 2010 ; 59 : 2597-602.
    • Nehiri T., Duong Van Huyen J.P., Viltard M., Fassot C., Heudes D., Freund N., G. Deschênes , Houillier P., Bruneval P. And Lelièvre-Pégorier M. Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in rat offspring. Diabetes, 2008 ;57 : 2167-75.

     

    Collaborations:

    • EA 3859, Labratoire HIFIH (Hémodynamique, Intéraction Fibrose et Invasivité tumorale Hépatique), Angers
    • CHU Angers (services d’endocrinologie, de pédiatrie et de chirurgie pédiatrique)
    • Institut d’Enzymologie, Budapest, Hongrie